CA2100338A1 - Non ionic iodized agents for x-ray contrasting, method for preparing them and galenical compositions containing them - Google Patents
Non ionic iodized agents for x-ray contrasting, method for preparing them and galenical compositions containing themInfo
- Publication number
- CA2100338A1 CA2100338A1 CA002100338A CA2100338A CA2100338A1 CA 2100338 A1 CA2100338 A1 CA 2100338A1 CA 002100338 A CA002100338 A CA 002100338A CA 2100338 A CA2100338 A CA 2100338A CA 2100338 A1 CA2100338 A1 CA 2100338A1
- Authority
- CA
- Canada
- Prior art keywords
- dihydroxypropyl
- bis
- carbamoyl
- triiodoisophthalamide
- hydroxyethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
Abstract
ABSTRACT
The invention refers to new iodinated, non-ionic X-ray contrasting agents with a dimeric structure with the general formula I, in which the bridging link is glycine or an N-substituted glycine I
where R1 is a linear or branched polyhydroxyalkyl of 2 to 4 carbon atoms, R2 is a hydrogen, methyl or linear polyhydroxyalkyl residue of 2 to 3 carbon atoms, R3 and R8, which may be the same or different are hydrogen, methyl or 2-hydroxyethyl, R4 is a linear or branched polyhydroxylalkyl of 2 to 4 carbon atoms, R5 is methyl, hydroxymethyl or methoxymethyl, and R6 and R7 which may be the same or different are hydrogen, methyl, hydroxyethyl or 2,3-dihydroxypropyl, R2 and R5 together being able to form a group of the type where n may be from 0 to 3.
The invention also refers to procedures for the obtention of products of formula I, and preparations which are pharmaceutically acceptable that contain these products.
The invention refers to new iodinated, non-ionic X-ray contrasting agents with a dimeric structure with the general formula I, in which the bridging link is glycine or an N-substituted glycine I
where R1 is a linear or branched polyhydroxyalkyl of 2 to 4 carbon atoms, R2 is a hydrogen, methyl or linear polyhydroxyalkyl residue of 2 to 3 carbon atoms, R3 and R8, which may be the same or different are hydrogen, methyl or 2-hydroxyethyl, R4 is a linear or branched polyhydroxylalkyl of 2 to 4 carbon atoms, R5 is methyl, hydroxymethyl or methoxymethyl, and R6 and R7 which may be the same or different are hydrogen, methyl, hydroxyethyl or 2,3-dihydroxypropyl, R2 and R5 together being able to form a group of the type where n may be from 0 to 3.
The invention also refers to procedures for the obtention of products of formula I, and preparations which are pharmaceutically acceptable that contain these products.
Description
2100338 ; ; ~
.
New iodinated, non-ionic x-ray contrast media, a method for ~ .
their preparation and galenic compositions which contain them.
SCOPE OF~ INV~ION ~:
The present invention refers to new iodinated, non- ~
ionic x-ray contrast media with a dimeric structure, . :
pharmaceutical compositions which contain them, and a :.
preferred method for preparing them.
.
These media are intended for contrasting the body structures and organs of the body by means of intravenous administration (specially in urography, and vascular and peripheral angiography), as also in other radiological techniques, such as lymphography and myelography, investigation of the valves of the heart, as also neuro~
radiological techniques, intended to show up e~pty spaces consisting of cavities containing cephalorhachidian liguid, as also in bronchography, hysterosalpingography and arthrography.
. . .
~ACRGROUND
For the X-ray examination oP, for example, the efferent urinary organs or the angiographic examination of blood vessels, very compatible salts of 2,4,6-triiodo-benzoic acids have been developed. However, these ionic compounds, when used at a high dosage, are not tolerated without side-~` 25 : effects, al~hough their toxicity is generally low.
, An adequate display of not only the vascular system : ~ and the efferent urinary system, but also of the cerebro-~ spinal cavities and other systems, requires the use of high30 doses of the contrasting agent or highly concentrated solutions o~ the same. At the same time, the physical-chemical properties of contrasting agents become important, because they are responsible for serious " ., . , . .. ~ " .. , . .. . . , ...... . ; .~ .. , , .. , ~. .. . . :
21003~8 pharmacological effects, such as pain, a lowering of blood pressure, injury of the blood vessels, and ~any other effects. -In neuroradiology, the empty spaces consist of various cavities which connect with the central nervous system. They include, for example, the ventricles of the brain, the cisterns, the sub-arachnoidal space around the brain, as also the spinal canal. The radiological examination of these cavities is usually subdivided into three main groups:
ventriculography, cisternography and myelography.
The demands made on the physical -chemical properties of the contrasting agents, such as viscosity, which has been adapted to make them not only easier to use, but also to avoid premature emergence from the empty spaces it is wished to display, and the correct osmolality to reduce the overall effect of osmotic processes, are especially important. However, contrasting agents should not remain for too long in the spinal canal, which is the case with the iodinated oils which have been used up till now, and which are insoluble in water and metabolise slowly, Finally, as will readily be understood, the demands made regarding the compatibility of x-ray contrasting agents are specially high in neuroradiology. The amounts of X-ray contrasting agents are large in comparison with the amount of liquid in the space being examined.
SUMMARY OF THE ~NVENTION
To avoid these drawbacks, non-ionic, water-soluble contrasting agents have been developed, which present a series of advantages:
They have a lower osmotic pressure and, therefore, ~ .
':
.
New iodinated, non-ionic x-ray contrast media, a method for ~ .
their preparation and galenic compositions which contain them.
SCOPE OF~ INV~ION ~:
The present invention refers to new iodinated, non- ~
ionic x-ray contrast media with a dimeric structure, . :
pharmaceutical compositions which contain them, and a :.
preferred method for preparing them.
.
These media are intended for contrasting the body structures and organs of the body by means of intravenous administration (specially in urography, and vascular and peripheral angiography), as also in other radiological techniques, such as lymphography and myelography, investigation of the valves of the heart, as also neuro~
radiological techniques, intended to show up e~pty spaces consisting of cavities containing cephalorhachidian liguid, as also in bronchography, hysterosalpingography and arthrography.
. . .
~ACRGROUND
For the X-ray examination oP, for example, the efferent urinary organs or the angiographic examination of blood vessels, very compatible salts of 2,4,6-triiodo-benzoic acids have been developed. However, these ionic compounds, when used at a high dosage, are not tolerated without side-~` 25 : effects, al~hough their toxicity is generally low.
, An adequate display of not only the vascular system : ~ and the efferent urinary system, but also of the cerebro-~ spinal cavities and other systems, requires the use of high30 doses of the contrasting agent or highly concentrated solutions o~ the same. At the same time, the physical-chemical properties of contrasting agents become important, because they are responsible for serious " ., . , . .. ~ " .. , . .. . . , ...... . ; .~ .. , , .. , ~. .. . . :
21003~8 pharmacological effects, such as pain, a lowering of blood pressure, injury of the blood vessels, and ~any other effects. -In neuroradiology, the empty spaces consist of various cavities which connect with the central nervous system. They include, for example, the ventricles of the brain, the cisterns, the sub-arachnoidal space around the brain, as also the spinal canal. The radiological examination of these cavities is usually subdivided into three main groups:
ventriculography, cisternography and myelography.
The demands made on the physical -chemical properties of the contrasting agents, such as viscosity, which has been adapted to make them not only easier to use, but also to avoid premature emergence from the empty spaces it is wished to display, and the correct osmolality to reduce the overall effect of osmotic processes, are especially important. However, contrasting agents should not remain for too long in the spinal canal, which is the case with the iodinated oils which have been used up till now, and which are insoluble in water and metabolise slowly, Finally, as will readily be understood, the demands made regarding the compatibility of x-ray contrasting agents are specially high in neuroradiology. The amounts of X-ray contrasting agents are large in comparison with the amount of liquid in the space being examined.
SUMMARY OF THE ~NVENTION
To avoid these drawbacks, non-ionic, water-soluble contrasting agents have been developed, which present a series of advantages:
They have a lower osmotic pressure and, therefore, ~ .
':
2 1 ~ 8 cause less pain and less damage to the endothelium. Moreover, their concentration in the urine is higher and, in the case : - -of a sub-arachnoidal injection, arachnoiditis rarely occurs.
In the case of myelography, when non-ionic contrasting agents are used, there is only a slight tendency towards convulsive states (epilepto-genicity) es observedO However, with the METRIZAMIDE ~2-(3-acetamido-2,4,6-triiodo-5-~N-methyl- :
acetamido]-benzamido)-2-deoxi-D-glucose) or IOPAMIDOL ~bis-[1,3-dihydroxy-propylamide] of 5-~-hydroxypropionyl-amino- . ~:
2,4,6-triiodo-isophthalic acid~, it has not been possible, in - .
angiography and myelography applications, to prepare sufficiently concentrated and X-ray-opaque solutions, which were not also hypertonic in relation to blood and to the ~ -~
cephalorhachidian fluid. .~`
' -These agents, in spite of being strongly hydrophilic and of :~
low osmotic pressure, are highly viscous or barely soluble and have certain toxic effects. ~ .
As a patent which describes important non-ionic - -agents like the ones just mentioned, and which are also dimers, there is the Spanish Patent 381.202, which refers to compounds with the general formula:
:.
CON ~2 : .
L,~
I
~ ~:
':
where R1 and R2 can be identical or different, and can be ;
:, 2ro~3r~s ~
hydrogen atoms or alkyl, hydroxyalkyl or acyloxialkyl groups, and R3 and R4 can also be identical or different, are hydrogen atoms, acylamino groups with the formula NR5Ac where R5 is a hydrogen atom or an alkyl, hydroxyalkyl or acyloxialkyl group or an acyl group and Ac is the acyl group;
acylaminomethyl groups with the formula CH2NR5Ac; or carbamoyl groups with the formula CoNR6R7 in which R6 and R7 have the same character as R5.
In the publication of European Patent EP-A1-002992, non-ionic compounds with the following general formula are described:
(OH)2 3-al.~-NHCO coNH-a -;-(OH)2-3 ~ ~I-a~lene -~t I ~
! OE~ ) 2 _ 3 - a lk - NHCC C~ 3 T COh'.-. - 2 1 '< - ~ OH ) 2 - ~
CH-C~ C:1-O~.
R R
~ -where, (OH)2 3-alk represents 1,3-dihydroxy-isopropyl, 2,3-dihydroxy-propyl or 1,3-dihydroxymethyl-isopropyl;
R represents a hydrogen or methyl; and "alkylene" represents a divalent alkylene radical of 2 to 10 carbon atoms, which may be replaced by hydroxy functions, or a mono-, di-, or polyoxa-alkylene radical of 4 to 12 atoms of carbon which may be substituted with hydroxy functions, these being intended as co~Q9~ '~or vasography, urography, bronchiography and to reveal body cavities and places where body liquids accumulate, by being opaque compounds. It is pointed out that these compounds are highly soluble in water, have the highest compatibility and slight osmolality.
In the publication of European Patent EP-A1 0,049.745 which is the equivalent of Spanish Patent 460.007, non-ionic compounds with the following general formula are described:
:
. "
\ N ~ R ~ f R- ~. . -.
CO (~0 ~N-C0~ I~-C0- C-Cv-N ~o ~
I R3 R3 I ~: -where, R represents a lower mono- or poly-hydroxyalkyl radical with a linear or branched chain;
R2 represents a hydrogen atom, a lower alkyl radical or Rl;
R3 represents a lower mono- or di-hydroxyalkyl radical; and X represents a direct bond or an alkylene linear or branched chain which may be interrupted by one or various oxygen atoms and replaced with hydroxy or alkoxy groups.
A compound which is included in this general formula which has been mentioned especially is that known under the name of IOTROLAN, with the formula N,N'-dimathyl-N,N'-bis[3,5-(1-hydroxymethyl-2,3-dihydroxy-propyl-carbamoyl) 21003~8 -2,4,6-triiodo-phenyl]-diamide of malonic acid, in which therefore:
X = methylene, Rl = R2 = 1-hydroxymethyl-2,3-dihydroxy-propyl and R = methyl.
It is pointed out that these compounds are suitable -for providing opacity as X-ray contrasting agents.
In the publication of European Patent EP-A1-108.638 non-ionic compounds with the following general formula are described:
RNHCO OCNHR
I ~ I I ~ I
/~\ N - A - :`1 ~ .
RNHCO I i ¦ OCNHR
CC CO
where 30 R is a -CH(CH2OH)2[1,3,dihydroxy-2-propyl], -CH2CH(OH)CH2OH[ 2, 3-dihydroxypropyl] group; and A is a -CH2CH(OH)CH2-[2-hydroxypropane-1,3-diyl] or -CH2CH(OH)CH(OH)CH2-[2,3-dihydroxy-butane-1,4-diyl], '' which are indicated as having good opacity characteristics 35 as contrast media for x-rays.
Finally, in the document of European Patent 33.426, compounds with the following general formula A [and B] are described:
'` ' '::
.
, . . . , _, ,, _ .. .. , .. _, _ .. ,_ _, . . ........ _ , ,,, , _ . ,, _ _.. ~ . . ... _ 1 ~ '. ; i' "' . ~ . " ' : ' . ' ' . , .. . `' . ` ' . " .; ' ' .
~100338 .. ;-CONT ~ X--C~N I : . -A f~- ~ R
where, 15 Rl R3 ,-D is - CONT or - NCOE ;
T is 1,3,4-trihydroxybut-2-yl; -Rl is hydrogen, methyl or ethyl:
E is Cl 3 alkyl, usually Cl 2 alkyl, which may be substituted with one or two OH, alkoxyl 3 or Cl 3 groups; and X is a simple or Cl 2 alkylene group, preferably Cl 2 which containsfrom nought to two Cl_3 hydroxy and/or alkoxy groups, each carbon atom having a maximum of one '-substitute.
,, . ' ,~ ' To prepare these compounds, dioxolane-type protector groups are used for the vicinal OH groups.
0 ~ ;;
Included in these compounds the aforementioned IOTROLAN is to be found.
The authors of the present invention have discovered a new group of non-ionic dimeric compounds derived from -dicarbamoyl-triiodoisophthalic acid which incorporate a glycine~ bridge in their molecule, and have the general formula I:
: :
. . .. _ . . _ _ . _ . _ . .. , . , , . . . _ . . .. _ :
OR 210Q3?~
Il ~8 1l R
C-N~ C-N~ 3 )~ C - N - C-A2 - C - N~C C
R2 R~ R~ r N ~
?.,~ ."
where, `-Rl represents a linear or branched C2-C4 polyhydroxylalkyl radical:
R2 represents hydrogen, methyl or a linear C2-C3 polyhydroxyalkyl radical, or 2-hydroxy-3-methoxypropyl; .. .
R3 and R8 are the same or different, and represent hydrogen, .
methyl or 2-hydroxyethyl; :.
R4 represents a linear or branched C2 to C4 polyhydroxy- ~
alkyl radical; :
R5 represents methyl, hydroxymethyl or methoxymethyl; .
R6 and R7 are the same or different, and represent hydrogen, ~. :
methyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.
O ~ .
R2 and R5 together form a group of the type ) ~
~ (CH)n where n can be 0 to 3.
" ;
It has been shown that these compounds have a -higher iodine content and that their aqueous solutions have . `~~; ~ lower viscosities to those compounds previously indicated, as :
also only slight toxicity, higher solubility in water and, above all, they:are very economical to synthesise and purify. -~
:~ .
The very low osmolality is achieved because of the reduction of the number of dissolved ~articles. Owing to this reduction in osmolality, a significant reduction in side-effects due to ~issue damage, deformation of erythrocytes and vasodilatation can be achieved, it being possible to make this reduction larger in the products of this~:invention when~the ratio of iodine atoms to total particles dissolved;is 6:1.
:~; ~ : .. .
2~0~
In addition, it has been observed that the compounds of the present invention have a pronounced effect on the intra-molecular aggregation resulting in actual osmolalities of the solutions which are even lower than the theoretical one, resulting, in those cases examined, in solutions which are hypotonic with respect to blood or to the cephalorhachidian fluid. : -Another important aspect, which has been already quoted, is the viscosity of aqueous solutions. In general, this parameter increases with the number of OH groups present , in the molecule, but as these groups are essential to achieve the necessary hydrosolubility of the compounds, in most cases it is necessary to make a compromise; in some cases, the substitution of an OH group by an -OCH3 group has even resulted in compounds which are very soluble without a ~
substantial increase in viscosity. ~-It has been shown that the compounds investigated present a series of isomeric forms due to the existence of chiral carbon atoms (optical isomers), as also the presence of restricted rotation of the N-CO bonds due to the proximity of the bulky iodine atoms (isomers E and Z), the invention extending also to the isomeric forms of these compounds, including the optically active, racemic and "meso" forms.
The solubility of the compounds in water at 20~C
easily reaches values of ~00 mg of I/ml apparently without a tendency to crystallise due to supersaturation. It is assumed that there a relationship between the solubility in water and the large number chemically isomeric species.
Similarly, their toxicity, measured as the lethal dose at 50%, LD50, is much reduced as has been shown by the studies carried out.
.. . . . . . .
21003~8 The invention also extends to galenic compositions which include compounds with the general formula I, at concentrations between 100-400 mg of I/ml, and incorporate pH
stabilisers, such as the buffer Tris (=tris(hydroxymethyl)-aminomethane and its phosphate, citrates and bicarbonatesalts, as well as sterile, apyrogenic water. The formulation may also incorporate complexing agents for heavy metals, for example, the sodium and/or calcium salts of ethylenediaminetetracetic acid, and other chelating agents which are pharmaceutically acceptable.
It is evident that these compositions, because of the higher proportion of iodine ccntained in compounds of Formula I, that for a given concentration of iodine per millilitre, less quantity of active substance is required, resulting in an economy in the preparation of these compositions.
From these compounds, those preferred are those from Examples 1 - 38, whose critical properties (solubility, viscosity, osmolality and iodine concentration as a -percentage) have been found to be very advantageous. To facilitate identification, they are summarised in the following table, Table I, where the equivalence of the symbols Rl to R8, and the value os the aforesaid properties are given.
As particularly of interest, the compounds of Examples 9, 11 and 36 stand out. - -. ' ~ ','.
' .:
~ . 2 1 0 ~ 1 3 3~8 o~ o ~ ~:
~ . '.~
.~ ~ _ . .
~ ~ ~a ~ ~D m ~ 3 ~
~ ~ - ~ ~
~ 8 z ~ ~3 N ~ ~ N ¦ ~
\0/ _ Z _ ._ "' ' ';
_ ~ ~
o_~/ O\~ ~, . :,' , , \~ ( ~ = a~ a~ ~ -0~ _ _ _ ' u_~ ~ _ _ _ = = = _ z=~~~ ~ ~ ~ 0 Z-~ ~
. ~ _ ' : ' D _ = D _ ..
~ : ~N _ _ _ Z _ ~ ~ ~
- ~: - -~z~ ~ - ~
~ ~ ~ x a T r~ T --T T _1~
.. ~ _ ., _ . _ , _ _, .~ __ .. _ .. . . . _ . __ __ _ _ . _ . _ . _ .. .. _ .. . . __ ... _ _ . _ ~
~ . . , ,, ...... ` '' , " ., ', "' ~' j ' ,'' ,'' ; , ' ",, ' ' :, ' ' ' . : ' '. ' ' ' ', . ' . . .', ,' ' . ' ' ' . . ', ; " . . ' , ' :, ' :: ': ' : .
. ~ :
. 210~3 8 .~ U~ ~ ~o ~ ~ ,` ..
~ .r U~ ~r ~ N _ O r~ u7 ' ., I O 1~ C~ ~ N N r~ 0~ ~ ~
_ ~ ~"''' -' ~ O _ U- ~0 N 0~ 01 ~D N ~5 0~ ~ o ~ ~ ~ ~o ~ r l ~ ''' .''"'.
`.'"
~P = s = = = = = = = I '. --_ . _ I ., ' ~ = a~ O a~ a~ ~ = = ¦
C-= _ L c ~ ~
CN N C L
:~7 8N ~ _~ C _ $ N _ 0 ._ , . .
N ~N CN 5~ _N ;~1 CN C ~ ~ CN
_ " :' "
1~) 2 2 _ ~ S = = = = ":
C:
O ~ ~ :~ = _. :~: _ = :5: = : ' " '' -a L~
~ ~ 3NB ~ ~a ~a ~a ~ ~a ~a =a =a , ~o ~ ~ 2 1 ~ û 3 ~ ' 8 1 . u~
_ ,., ii5'5 ~ , _ l ~ ~_ ,. . o ~
C~
D 4~ ~ r_ l l l l l O ~ _ O I~ I .
_ ~ = = _ = = = = = = = _ .
q _ ~ ~ ~ ~ !
~ a = = = = = = a a a l ~ ~
~ q q = = = a~ ~ ~, E~ q~ $ $
. ~ ~ q~ ~ q ~ ~ ~ = ~ ~ ~ a : ~0 ~ ~ _ __ .. . . I '' ' . ' ~ ~ ~ = ~ = = = = = ....
c ~ q q ~ q 8 ~ 1: ~ ~N ~ ~ ,, ~ ~ ~ 8 H . l _ __ : ~ ~ ~ 0 ~æ ~,., ~ ~0 ~~, ,~0 ~æ æ ~
ll r~ ~N ~ _, ~" ~ ~ _,~" _ c~-- C.~ ~_~ ~ C~ ~J O~ 1~-- ., ~ ~ ~3 ~3 ~3 c~3 ~} ~ ,~,3 ~3 ~,3 ~a ~a : ~
- .~. .. . .. . . . ,.. ; . . , .. ,, . . .. ~ . .. .... ............... ... .
~ . . ,, , ...,.. , ; . i. .-. -. . . .
21003~8 ~,c ~ ~ ~ o ~ o U. ' :' . ' ~ _ _ _ ,, ~,.'.-', oo~ l ) l ~ l u l ~ ~ l~n ' ' ' No _ _ N _ _ ~ 1:1 1~ l l i :? _ = _ _ = _ _ = _ _ ~ ,,,' .
~ o~ o o o~ = ~ r ~ r _ O N l l ~ .:, , ~ _ = Or~ Or _ r 3~ = or r ~ ~
J:~ ~ C qN ~ ol" C ~ O _rl ~
~ 0~ = ~ ~ ~ = S =
~ .r = . ~ 9~ ~k g~
~ _ _ _ . ' ¦ L~r ~a =a ~5 r ~ a ~a ~a ~a =a ~a ;~: -~ .
-:
210033$
~ C N O _ _ O ~O
. ~ _ _ oUo~ ~, U- V~ ~O U~ ~0 ~g g_ C_~ _l .~ ~_1(~ _ `D ~`1 O
8 ~ a o~ ~ ` ~ ' ~ :~ : ' a~
~ = 5 = :5: ~ = .-8" .
~ ~ ~ o~ o ~ ~ -~ ~ :, ~ ~ ~ ~ = ~ ~ .' ~ Orl O 8 ~ o ;
.! ~F~
r . = S
_ --8r'-o ~ = S ~ ' S =
~ ~ o ~ ~ 8 N ~ N 5~ N N
o a ~, l ~ , _ ~0~ ~0~ ~ 0~ _ ~
~ C~J-- ~ " ~ ~"N~ ~ ~ ~,~N
~ ~3 ~xi3 ~,,3 ~3 ~33 ~3 . '; ' ` ' ' ' ' ' 2-~6~8 To demonstrate the reduced intravenous to~icity, Sprague-Dawley rats of both sexes with a weight between 90 and 120 g were used, and which were administered the compounds via the caudal vein at a constant rate of 2.2ml/min (Salvesen S.
Acta Radiologica, Suppl. 362, page 73, 1980). After the injection, the animals were observed to record their immediate reactions and the respective mortalities were recorded during a period of seven days, followed by calculation of the lethal dose for 50% of the animals, LD50.
The most preferred compounds were studied, from Examples 9, 11 and 36, and they were compared with IOTROLAN as a reference which has already been mentioned. The physical~
chemical and toxicological data appear in the following table:
; . ,:: ., .:
.. .. .
- ,. . . . ,.. - - - . ~ ~ . . - ~ .- . - .. . .; .... . . . . .
210703~8 .
~ o ~ :~
~ ~q ~ ~ ~ :' --- ~ :
o~ ~ - - -- :
~3 ~ ~, N ~ N r~ ~ ~
E . j O H _ o e ~ _~ ~ _ :~ .
.
.
210Q~8 According to a preferred method, the compounds of -formula I are prepared by reacting a compound of formula II -. ~.
I ~ a II ;
R~ a with an acid chloride with the formula III --l8 R_~CN ~ ~ Cl III ;;~;
. . .: .
: . . :
in the presence of a basic catalyst, the radicals Rl to R8 having the signi~icance given previously.
During the reaction, the OH groups are protected as acetates or, when the OH groups are vicinal, as dioxepane. ~-~
These protective groups are easily eliminated by conventional ; 3c methods used in chemistry, such as hydrolysis.
The final compounds of general formula I are purified by treatment with ion-exchange resins, by conventional purification methods, or by means of preparative chromatoqraphy.
There follows a description of the preparation of ;~ ~ the preferred compounds mentioned in Table I.
.~ . .
. . . .
210l09338 Exam~le l N, N~ -bis-(2,3-dihydroxvmropyl)-N, N~ -dimethyl-5- ~ 3- ~N- ( 2,3-dihydroxy~ropyl)carbamoyll-5-methoxyacetamido-2,4,6-triiodo-S benzovlaminoacetamido~-2,4,6-triiodoisophthalamide (lCJ-1089) ~-a~ N- ~ 3 diacetoxvpropvl~-5-methoxyacetamido-2 4 6- ~ -triiodoisoohthalamovl ~ o~de.
Methcd I
To a solution of N-(2,3-diacetoxy-propyl)-~-amino-2,4,6-triiodoisophthalamoyl c.~loride (22.03g, 30 mmcl) in DMA (80 ml) cooled to 0-5 C, is slowly added a solution of methoxv2cetyl chloride (8 g, 90 Nmol) in DMA (20 ml). Once the addition has be~n completed, it is s~ --ad at room tempe-ature durin~ the night. The reaction medium is distributed between ethyl acetate (350ml) and wate (200 ml).
The 2aueous phase is ex~-acted with ethyl acet .e (3 x 50 ml) the or~anic extracts are combined and washed wl~:~ a 5~ sodium bicar~onate solution(2 x 50 ml) and a satura~ad solution cf sodium chloride (100ml). The product is dried cver anhydrous MgSO4 and the solvent is removed at reduced pressure. The product thus obtained is purified by recrystallisation from ethyl acetate (9O ml).
M.p.: 211/213 C. Yield: 62%
Method II
.
A mixture of methoxyacetic acid (3g.6 g, 0.4~ mol) and thionyl chloride (30.5 ml, 0.42 mol). is heated at 50 C ~or 35 two hours. It is cooled to room temperature and it is slowly add~d to a solution cooled to 0-~ C of N-( 2, 3 -diacPtoxy-propyl~-5-amino-2,4,6-triiodoisophthalamic acid (78.8 g, 0.11mol) in DMA (300 ml). Once the addition is concluded, it is stirred at room temperature until fully converted :
21~032g into N-(2,3-diacetoxypropyl)-5-methxyacetamidmid-2,4,6-triiodoisophthalamic acid (TLC with AcOEt/C~C13/AcOH 6:2:1) which is not isolated.
It is cooled aqain to 0-5 C and thionyl chloride ~32 ml, 0.44 mol) is slowly added, and stirring is maintalned for 30 minutes. The reaction medium is distributed bet-~een ethyl acetate (1120~1) and water (1060 ml). The aqueous phase is extracted with ethyl acetate (3 x 250ml) the organic extracts are combined and washed with sodium bicarbonate at 10~ (3 x 200 ml) and a satl~rated solution of sodium chloride (1 x 250ml). ~t is dried ove' anhydrous MqS04 and the solvent is removed at reduced pressure. The product thus cbtained is purifie~ by recrystallisation from ethyl acetate.
Yield: 75%.
b~ N N'-~is-(2~3-dihvdroxv~ro~vl~-~ N'-dimethvl-^-(3-rN-(2-3-dihvdroxv~ vl~carbamovl~-3-~ethcxvacetamido-2 4 6-triiodo-benzov~ noacetamido~-2 4,6-triiodoiso~hthalamide.
To a suspension o~ N,N'-bis-(2,3-dihvdroxy-propyl)-N,N'-dimethyl-~-aminoacetamido-2,4,6-t_iiodoisophthala~ide (3) (12 g, 0.015 mol) y and sodium carbonate decahydrate (13.1g, 0.046 mol) in DMA (60 ml), is added, with vigorous stirrin~, the compound previously described in example la) (13.5 g, 0.017 mol). It is stir_ed cont nuously at room te~perature until the ne~t day. It is filtP_ed, and the filtrate is concentrated to dryness at reduced pressure. The residue is dissolved in methanol/wate_ (1:1) y and is hydrolysed with 50% NaOH (pH 11.5) at 40 C. It is neutr~lised with concantrated hydrochloric acid (p~ 6.5) and evaporated to dryness at reduced pressure. The residue is dissolved in methanol and precipitated from isopropanol. Filte_ and dry in vacuo.
Yield: 70%.
The product obtained is purified by preparative liquid chromatography.
M.p.: 200 C (sinters)/ 230-257~C (deco~poses).
21~3~
Example 2 N N~-bis-(2 3-dihydroxypropylL-N~N~-dimethyl-5-(3-[N-~2~3-dihydroxypropyl~carbamoyll-5-hydroxyacetamido-2,4 6-triiodo-benzoylaminoacetamido)-2.4 6-triiodoisophthalamide (lCJ-1389 !
a) N-(2.3-diacetoxypropyl)-5-acetoxyacetamido-2.4.6-triiodo- -isophthalamoyl chloride Method I
To a solution of N-(2,3-diacetoxy-propyl)-5-amino-2,4,6-tri-iodoisophthalamoyl chloride (66.1g, o.O9o mol) in DMA (260 ml) cooled to 0-5 C, is slowly added acetoxyacetyl chloride (36.9g, 0.270 mol). Sitirring is maintained at room temperature until the next day. The reaction medium is distributed between ethyl acetate 400ml and water (800ml). It is extracted from the aqueous phase with ethyl acetate (3 x 250ml) and the combined organic extracts are washed with a 10% solution of sodium bicarbonate (2 x 200ml) and 10% sodium chloride (200ml). It is dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure.
The product obtained is cold recrystallised from chloroform.
! Yield: 88-90% M.p.: 202-204 C
~etho~ II
To a solution of N-(2,3-diacetoxypropyl)-5-amino-2,4,6-triiodoisophthalamic acid (65.6g, 0.092 mol) in DMA (250 ml) cooled to 0-~C, is slowly added acetoxyacetyl chloride (50g, 0.366 mol). Stirring is maintained at room temperature for 3-4h., until it is totally transformed into N-(2,3-diacetoxy-propyl)-5-acetoxyacetamido)-2,4,6-triiodoisophthalamic acid, which is not isolated.
It is cooled to 5-10 C, and thionyl ~hloride (26.5 ml, 0.366 mol) is slowly added and maintained at this temperature for 45 minutes.
` 210~338 The product is isolated from the reaction medium in the same manner as in Method 1. Yield: 75%.
.
b) N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-S-(3-rN-(2,3-dihydroxypropyl)carbamoyl~-5-hydroxyacetamido -2,4,6-triiodobenzoylaminoacetamido)-2,4,6-triiodoisophthalamide.
Following the general procedure given in example lb) and starting from N,N'-bis(2,3-dihydroxy-propyl)-N,N'-dimethyl-5-aminoacetamido-2,4,6-triiodoisophthalamide (3) (20 g, 0.025 mol) and the compound described in example 2 a) (23.2 g, 0.028 mol). Gross yield: 70%. m.p.. 261-274 C (decomposes) ... ... .
Exam~le 3 N N'-~is-(l-hydroxymethyl-2 ! 3-dihvdroxy~ropvl)-s-(3rN-(2~3-dihvdroxy~rooyl)carbamoyll-5-hydroxyacetamido-2,4,6-triiodo-~enzovlaminoacetvl-N-methylamino1-2,4,6-tri1QdQiso~hthalamide. (lCJ-190 a) ~-c~loroacetyl-N-methylamino-2,4,6-triiodoiso~hthalovl chloride.
., '..
60 g (104.74 mmol) of 5-N-methylamino-2,4,6-triiodo isophthalic acid is suspended in 400 ml of ethyl acetate and S1.8 g (435.74 mmoles) of thionyl chloride are added. It is heated to maintain reflux for 4 hours. A solution of dichloride is :
obtained. Thin-layer chromatography is carried using to}uene-methanol (4:1) as an eluent. The product with an Rf=0.90 is observed. It is cooled to 60 C and 35.5 q (314.33 mmoles) chloroacetyl chloride is slowly added. It is , returned to reflux te~perature and heated f~r 7 hours.
After 1 hour, the desired product star~s to crystallise.
:' Thin-layer chromatography is carried out using toluene- -methanol (4:1) as an eluent, and the product with an Rf= 0.78 is observed.
The ethyl acetate is partially distilled off. -~
"'~ " ' . . .
21~0338 The product is cooled to room temperature and filtered off.
Obtained: 61g (molar yield: 84~).
b) N.N'-bis-(7-hydro~y=~,4-dimethyl- 3.5-d oxe~anyl~-5-chlo~oacetyl-N-methylamino -2.4 6-triiodois~p~thalamide.
185 g (269.59 mmol) of 5-chloroacetyl-N-methylamino-2,4,6-triiodoisophthaloyl chloride are suspended in 555 ml of dioxane. 169.7 g of sodium car~onate decahydrate (593.10 mmol) and 95.6 g of 2,2-di-methyl-;-hydroxy-6-amino-1,3 dioxepane (5~3.10 mmol) are added and heated to 50 C. After 8 hours total conversion to diamide occurs. Thin-layer chromatography is carried out using acetone-ethyl acetate (1:1) as an eluent, and a product with an Rf of 0.70 is observed. Salts are filtered off and the solvent is 1~ evaporated to dryness.
Obtained: 226 g (Molar yield: 90~) c~ N~N~-bis-(l-hYdroxymethyl-2 3-dihydroxyproDv1!-5-chloroacetyl-N-methvlamino-2.4.6-triiodoiso~hthalamide.
100 g of the compound from example 3b) are taken and dissolved in 300 ml of methanol. 3S% hydrochloric acid is added until a pH-l is reached, and the mixture is heated at 40-C until total hydrolysis is achieved with a quantitative yield, The product is evaporated to dryness.
Obtained: 91,4 g (quantitative3.
Thin-layer chromatography under the same conditions as in example 3b) retains the product totally at the origen. Using chloroform-methanol (3:2) as an eluent results in an Rf =0.57 d) N.N'-bis-(1-hydroxymethvl-2.3-dihydroxvpropvl)-5-amino-acetyl-N-methylamino-2 4 6-triiodoiso~hthalamide.
23.6 g of the compound of example 3c) (27.58 mmol) are dissolved in 27S ml of aqueous ammonia, and then heated at ~0-C for 24 hours. The product is evaporated to dryness.
The product is dissolved in methanol, the hydrochloride is formed and the solvent is removed.
..... . . . . ~ .. . . .. . . . . .
Thin-layer chromatoqraphy usin~ chloroform~-methanol (3:2~
as a eluent produces a stain at the origen. Using methanol as an eluent it produces a stain retained at R~=0.65. ~
Obtained: 12.5 g (molar yield: 54~) -e) N,N'-bis-(l-hydroxymethyl-2,3-dihydroxvproDyll-5-~3- ~N- :
(2~3-dihydroxypropyl)carbamovl]-5-hydroxyacetamido-2~4~6-triiodobenzoylaminoacetyl-N-methylamino~-2,4,6-triiodo-isophtalamide. (ICJ-290) '., 14 g (16.74 mmol) of the c~mpound from example 3d) is suspended in 60 ml of dimethylformamide, and 9.58~ (33.4a mmol) of sodium carbonate are added. The product is stirred for S min. and lS.1 g (18.08 mmol) of the produc~ from example 2a) are added. It is stirred at room temperature until the reaction is complete (24 hours).
......
The salts are filtered off, and the solvent which contains the dime- is evaporated to dryness. It is dlssolved in 100 -ml of methanol. It is then filtered and precipitated with 600 ml of isopropanol. It is filte~ed, drained and dried.
Crude product: 26 g (Yield: 95%).
The acetate grouos are hydrolvsed and the substance is puri~ied by preparative liquid c~romatography.
Pure produ~t: 12 g (molar yield: 48%).
Example 4 ,, N,N'-bis-L~h~droxvmethvl-~.3-dihvdro~_~ro~vl)-~-(3-~N-(2.3-, dihvdroxv~roovl~carbamovli-5-mç,thoxyacetamj~ ~-2~4 6- ::~
triiodoben~o laminoacetvl-~-met~v~ o~-2.4 6-triiodo-iso~hthalamide. ~lCJ- 290) -15.2 g (18.18mmol) of the compound from example 3d)is suspended in 70 ml of DMF, and 10.38 g (36.28 mmol)of -~
sodium carbonate decahydrate is added. The mixture is stirred for 5 ~in. and 15.8 g (19.59 mmol) of the compound from example la)is added. It is stirred at room tempe~ature ~-; 40 until the reaction is complete. (28 hours).
:
2fO~338 The salts are filtered off and the solvent is evaporated. The product is then dissolved in lO0 ml of methanol (inorganic salts are again filtered off) and it is precipitated in 600 ml of isopropanol. It is filtered off and dried.
Crude product: 27 g (Yield: 92%), The acetate groups are hydrolysed and the product is purified by preparative liquid chromatography.
Pure product: 13 g (molar yield: 47%).
Example 5 N.N'-~is-(2.3-dihydroxye~ro~vll-N.N'-dimethyl-5-~3-rN-tl-hydroxy~ethyl-2.3-dihydroxv~roovl~carbamo~11-5-methoxyace-tamidQ -2.4.6-triiodo~enzovlaminoacetamido~-2.~.6-triiodo-iso~hthalamide. flCJ -2489~
a) N-(4,4-dimethyl-7-hydroxy- 3,5-dioxepanyl)-5-methoxy-acetamido-2,4,6-triiodoisophthalamoyl chloride ~-To a cold solution of 5-methoxyacetamido-2,4,6-triiodo-isophthaloyl chloride (30.05 g, ~ mmol) in DMA (150 ml), a solution of 6-amino-2~2-dimethyl-l~3-dioxepane-5-ol (2) (7.98g 49.5 mmol) and triethylamine (4.55 g, 45 mmol) in DMA (30 ml) is slowly added. It is stirred for 2 hours and the reaction medium is distributed between ethyl acetate (400 ml) and water (500 ml). The aqueous phase is extracted with ethyl acetate (2 x 50~1) and the combined organic extracts are washed with a 5% solution of sodium bicarbonate (50ml) and saturated sodium chloride (50 ml). It is then dried over anhydrous magnesium sulphate and dried under reduced pressure. The product thus obtained is dried in vacuo.
Yield: 67% m.p.: 230-C (decomposes).
b ) N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-(3-~N-(l-hydroxymethyl-~,3-dihydroxypropyl)carbamoyl)-5-methoxy-acetamido -2,4,6-triiodobenzoylaminoacetamido)-2~4~6-triiodo- -isophthalamide, Following the general procedure described in example lb) and '$
starting from N,N'-bis(2,3-dihydroxy-propyl)-N,N'-dimethyl-S-aminoacetamido -2,4,6-triiodoisophthalamide (20 g, 0.025 mol) and the compound described in example Sa) (22.1 g, 0.088 mol), a partially-protected compound is obtained (Yield 73~) which is treated with hydrochloric acid diluted in methanol. The resulting product is purified by preparative liquid cromatography.
M.p.: 263-2~5 C. (decomposes) . .
Ex~m~Le 6 ~,N'-bis-(2.3-dihydroxy~ro~vlt-5-(3-rN-(1-hydroxvmethyl-2.3-dihydroxv~ro~yl!ca~a~oyll-5-methoxyacetamido-2,4 6-triiodo-benzoyla~L~oacetamidol-2.4.6-triiodoiso~hthalamide (lC~-20~21 '.; . ' 13.4 g ~47.8 ~mol) of sodium carbonate decahydrate are added to a solution of 11.9 g (15.6 mmol) of N,N'-bis-~2,3-dihydroxypropyl) -5-aminoacetamido -2,4,6- triiodoisophthal-amide in 60 ml of DMU. It is stirred vigorously for about 10 minutes and 14.8 g (18.7 mmol) of the compound described in example 5a) are then added. S.irring is continued during a whole night. The solid is filtered off and washed with methanol and the solvent is removed at reduced pressure. The residue is dissolved en 50 ml of methanol and the product precipitated with S00 ml of isopropanol. After filtering, the solid is washed with ethyl ether and dried in vacuo over phosphorus pentoxide, to obtain 18.8g of a sIightly coloured solid (81%). This solid is hydrolysed in a hydrochloric acid ~edium stirring at room temperature overnight. It is neutralised and the solvent is eliminated at reduced pressure. The residue is purified by preparative liquid chromatography. The fraction that contains the product is evaporated to dryness to obtain 10 g of product of with a chromatographic s~rength greater than 99~ with an m.p. >260-C
; 35 (which sinters at 254 C) .
Example 7 N.N'-bis-(1-hydroxy~thy1-2.3-dihvd~o~ypropy1t-5-~3-~N~
"' ` ' ' ' ~'' ' ' ~ ' . . . ' ", , -'!, . . . .. .
In the case of myelography, when non-ionic contrasting agents are used, there is only a slight tendency towards convulsive states (epilepto-genicity) es observedO However, with the METRIZAMIDE ~2-(3-acetamido-2,4,6-triiodo-5-~N-methyl- :
acetamido]-benzamido)-2-deoxi-D-glucose) or IOPAMIDOL ~bis-[1,3-dihydroxy-propylamide] of 5-~-hydroxypropionyl-amino- . ~:
2,4,6-triiodo-isophthalic acid~, it has not been possible, in - .
angiography and myelography applications, to prepare sufficiently concentrated and X-ray-opaque solutions, which were not also hypertonic in relation to blood and to the ~ -~
cephalorhachidian fluid. .~`
' -These agents, in spite of being strongly hydrophilic and of :~
low osmotic pressure, are highly viscous or barely soluble and have certain toxic effects. ~ .
As a patent which describes important non-ionic - -agents like the ones just mentioned, and which are also dimers, there is the Spanish Patent 381.202, which refers to compounds with the general formula:
:.
CON ~2 : .
L,~
I
~ ~:
':
where R1 and R2 can be identical or different, and can be ;
:, 2ro~3r~s ~
hydrogen atoms or alkyl, hydroxyalkyl or acyloxialkyl groups, and R3 and R4 can also be identical or different, are hydrogen atoms, acylamino groups with the formula NR5Ac where R5 is a hydrogen atom or an alkyl, hydroxyalkyl or acyloxialkyl group or an acyl group and Ac is the acyl group;
acylaminomethyl groups with the formula CH2NR5Ac; or carbamoyl groups with the formula CoNR6R7 in which R6 and R7 have the same character as R5.
In the publication of European Patent EP-A1-002992, non-ionic compounds with the following general formula are described:
(OH)2 3-al.~-NHCO coNH-a -;-(OH)2-3 ~ ~I-a~lene -~t I ~
! OE~ ) 2 _ 3 - a lk - NHCC C~ 3 T COh'.-. - 2 1 '< - ~ OH ) 2 - ~
CH-C~ C:1-O~.
R R
~ -where, (OH)2 3-alk represents 1,3-dihydroxy-isopropyl, 2,3-dihydroxy-propyl or 1,3-dihydroxymethyl-isopropyl;
R represents a hydrogen or methyl; and "alkylene" represents a divalent alkylene radical of 2 to 10 carbon atoms, which may be replaced by hydroxy functions, or a mono-, di-, or polyoxa-alkylene radical of 4 to 12 atoms of carbon which may be substituted with hydroxy functions, these being intended as co~Q9~ '~or vasography, urography, bronchiography and to reveal body cavities and places where body liquids accumulate, by being opaque compounds. It is pointed out that these compounds are highly soluble in water, have the highest compatibility and slight osmolality.
In the publication of European Patent EP-A1 0,049.745 which is the equivalent of Spanish Patent 460.007, non-ionic compounds with the following general formula are described:
:
. "
\ N ~ R ~ f R- ~. . -.
CO (~0 ~N-C0~ I~-C0- C-Cv-N ~o ~
I R3 R3 I ~: -where, R represents a lower mono- or poly-hydroxyalkyl radical with a linear or branched chain;
R2 represents a hydrogen atom, a lower alkyl radical or Rl;
R3 represents a lower mono- or di-hydroxyalkyl radical; and X represents a direct bond or an alkylene linear or branched chain which may be interrupted by one or various oxygen atoms and replaced with hydroxy or alkoxy groups.
A compound which is included in this general formula which has been mentioned especially is that known under the name of IOTROLAN, with the formula N,N'-dimathyl-N,N'-bis[3,5-(1-hydroxymethyl-2,3-dihydroxy-propyl-carbamoyl) 21003~8 -2,4,6-triiodo-phenyl]-diamide of malonic acid, in which therefore:
X = methylene, Rl = R2 = 1-hydroxymethyl-2,3-dihydroxy-propyl and R = methyl.
It is pointed out that these compounds are suitable -for providing opacity as X-ray contrasting agents.
In the publication of European Patent EP-A1-108.638 non-ionic compounds with the following general formula are described:
RNHCO OCNHR
I ~ I I ~ I
/~\ N - A - :`1 ~ .
RNHCO I i ¦ OCNHR
CC CO
where 30 R is a -CH(CH2OH)2[1,3,dihydroxy-2-propyl], -CH2CH(OH)CH2OH[ 2, 3-dihydroxypropyl] group; and A is a -CH2CH(OH)CH2-[2-hydroxypropane-1,3-diyl] or -CH2CH(OH)CH(OH)CH2-[2,3-dihydroxy-butane-1,4-diyl], '' which are indicated as having good opacity characteristics 35 as contrast media for x-rays.
Finally, in the document of European Patent 33.426, compounds with the following general formula A [and B] are described:
'` ' '::
.
, . . . , _, ,, _ .. .. , .. _, _ .. ,_ _, . . ........ _ , ,,, , _ . ,, _ _.. ~ . . ... _ 1 ~ '. ; i' "' . ~ . " ' : ' . ' ' . , .. . `' . ` ' . " .; ' ' .
~100338 .. ;-CONT ~ X--C~N I : . -A f~- ~ R
where, 15 Rl R3 ,-D is - CONT or - NCOE ;
T is 1,3,4-trihydroxybut-2-yl; -Rl is hydrogen, methyl or ethyl:
E is Cl 3 alkyl, usually Cl 2 alkyl, which may be substituted with one or two OH, alkoxyl 3 or Cl 3 groups; and X is a simple or Cl 2 alkylene group, preferably Cl 2 which containsfrom nought to two Cl_3 hydroxy and/or alkoxy groups, each carbon atom having a maximum of one '-substitute.
,, . ' ,~ ' To prepare these compounds, dioxolane-type protector groups are used for the vicinal OH groups.
0 ~ ;;
Included in these compounds the aforementioned IOTROLAN is to be found.
The authors of the present invention have discovered a new group of non-ionic dimeric compounds derived from -dicarbamoyl-triiodoisophthalic acid which incorporate a glycine~ bridge in their molecule, and have the general formula I:
: :
. . .. _ . . _ _ . _ . _ . .. , . , , . . . _ . . .. _ :
OR 210Q3?~
Il ~8 1l R
C-N~ C-N~ 3 )~ C - N - C-A2 - C - N~C C
R2 R~ R~ r N ~
?.,~ ."
where, `-Rl represents a linear or branched C2-C4 polyhydroxylalkyl radical:
R2 represents hydrogen, methyl or a linear C2-C3 polyhydroxyalkyl radical, or 2-hydroxy-3-methoxypropyl; .. .
R3 and R8 are the same or different, and represent hydrogen, .
methyl or 2-hydroxyethyl; :.
R4 represents a linear or branched C2 to C4 polyhydroxy- ~
alkyl radical; :
R5 represents methyl, hydroxymethyl or methoxymethyl; .
R6 and R7 are the same or different, and represent hydrogen, ~. :
methyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.
O ~ .
R2 and R5 together form a group of the type ) ~
~ (CH)n where n can be 0 to 3.
" ;
It has been shown that these compounds have a -higher iodine content and that their aqueous solutions have . `~~; ~ lower viscosities to those compounds previously indicated, as :
also only slight toxicity, higher solubility in water and, above all, they:are very economical to synthesise and purify. -~
:~ .
The very low osmolality is achieved because of the reduction of the number of dissolved ~articles. Owing to this reduction in osmolality, a significant reduction in side-effects due to ~issue damage, deformation of erythrocytes and vasodilatation can be achieved, it being possible to make this reduction larger in the products of this~:invention when~the ratio of iodine atoms to total particles dissolved;is 6:1.
:~; ~ : .. .
2~0~
In addition, it has been observed that the compounds of the present invention have a pronounced effect on the intra-molecular aggregation resulting in actual osmolalities of the solutions which are even lower than the theoretical one, resulting, in those cases examined, in solutions which are hypotonic with respect to blood or to the cephalorhachidian fluid. : -Another important aspect, which has been already quoted, is the viscosity of aqueous solutions. In general, this parameter increases with the number of OH groups present , in the molecule, but as these groups are essential to achieve the necessary hydrosolubility of the compounds, in most cases it is necessary to make a compromise; in some cases, the substitution of an OH group by an -OCH3 group has even resulted in compounds which are very soluble without a ~
substantial increase in viscosity. ~-It has been shown that the compounds investigated present a series of isomeric forms due to the existence of chiral carbon atoms (optical isomers), as also the presence of restricted rotation of the N-CO bonds due to the proximity of the bulky iodine atoms (isomers E and Z), the invention extending also to the isomeric forms of these compounds, including the optically active, racemic and "meso" forms.
The solubility of the compounds in water at 20~C
easily reaches values of ~00 mg of I/ml apparently without a tendency to crystallise due to supersaturation. It is assumed that there a relationship between the solubility in water and the large number chemically isomeric species.
Similarly, their toxicity, measured as the lethal dose at 50%, LD50, is much reduced as has been shown by the studies carried out.
.. . . . . . .
21003~8 The invention also extends to galenic compositions which include compounds with the general formula I, at concentrations between 100-400 mg of I/ml, and incorporate pH
stabilisers, such as the buffer Tris (=tris(hydroxymethyl)-aminomethane and its phosphate, citrates and bicarbonatesalts, as well as sterile, apyrogenic water. The formulation may also incorporate complexing agents for heavy metals, for example, the sodium and/or calcium salts of ethylenediaminetetracetic acid, and other chelating agents which are pharmaceutically acceptable.
It is evident that these compositions, because of the higher proportion of iodine ccntained in compounds of Formula I, that for a given concentration of iodine per millilitre, less quantity of active substance is required, resulting in an economy in the preparation of these compositions.
From these compounds, those preferred are those from Examples 1 - 38, whose critical properties (solubility, viscosity, osmolality and iodine concentration as a -percentage) have been found to be very advantageous. To facilitate identification, they are summarised in the following table, Table I, where the equivalence of the symbols Rl to R8, and the value os the aforesaid properties are given.
As particularly of interest, the compounds of Examples 9, 11 and 36 stand out. - -. ' ~ ','.
' .:
~ . 2 1 0 ~ 1 3 3~8 o~ o ~ ~:
~ . '.~
.~ ~ _ . .
~ ~ ~a ~ ~D m ~ 3 ~
~ ~ - ~ ~
~ 8 z ~ ~3 N ~ ~ N ¦ ~
\0/ _ Z _ ._ "' ' ';
_ ~ ~
o_~/ O\~ ~, . :,' , , \~ ( ~ = a~ a~ ~ -0~ _ _ _ ' u_~ ~ _ _ _ = = = _ z=~~~ ~ ~ ~ 0 Z-~ ~
. ~ _ ' : ' D _ = D _ ..
~ : ~N _ _ _ Z _ ~ ~ ~
- ~: - -~z~ ~ - ~
~ ~ ~ x a T r~ T --T T _1~
.. ~ _ ., _ . _ , _ _, .~ __ .. _ .. . . . _ . __ __ _ _ . _ . _ . _ .. .. _ .. . . __ ... _ _ . _ ~
~ . . , ,, ...... ` '' , " ., ', "' ~' j ' ,'' ,'' ; , ' ",, ' ' :, ' ' ' . : ' '. ' ' ' ', . ' . . .', ,' ' . ' ' ' . . ', ; " . . ' , ' :, ' :: ': ' : .
. ~ :
. 210~3 8 .~ U~ ~ ~o ~ ~ ,` ..
~ .r U~ ~r ~ N _ O r~ u7 ' ., I O 1~ C~ ~ N N r~ 0~ ~ ~
_ ~ ~"''' -' ~ O _ U- ~0 N 0~ 01 ~D N ~5 0~ ~ o ~ ~ ~ ~o ~ r l ~ ''' .''"'.
`.'"
~P = s = = = = = = = I '. --_ . _ I ., ' ~ = a~ O a~ a~ ~ = = ¦
C-= _ L c ~ ~
CN N C L
:~7 8N ~ _~ C _ $ N _ 0 ._ , . .
N ~N CN 5~ _N ;~1 CN C ~ ~ CN
_ " :' "
1~) 2 2 _ ~ S = = = = ":
C:
O ~ ~ :~ = _. :~: _ = :5: = : ' " '' -a L~
~ ~ 3NB ~ ~a ~a ~a ~ ~a ~a =a =a , ~o ~ ~ 2 1 ~ û 3 ~ ' 8 1 . u~
_ ,., ii5'5 ~ , _ l ~ ~_ ,. . o ~
C~
D 4~ ~ r_ l l l l l O ~ _ O I~ I .
_ ~ = = _ = = = = = = = _ .
q _ ~ ~ ~ ~ !
~ a = = = = = = a a a l ~ ~
~ q q = = = a~ ~ ~, E~ q~ $ $
. ~ ~ q~ ~ q ~ ~ ~ = ~ ~ ~ a : ~0 ~ ~ _ __ .. . . I '' ' . ' ~ ~ ~ = ~ = = = = = ....
c ~ q q ~ q 8 ~ 1: ~ ~N ~ ~ ,, ~ ~ ~ 8 H . l _ __ : ~ ~ ~ 0 ~æ ~,., ~ ~0 ~~, ,~0 ~æ æ ~
ll r~ ~N ~ _, ~" ~ ~ _,~" _ c~-- C.~ ~_~ ~ C~ ~J O~ 1~-- ., ~ ~ ~3 ~3 ~3 c~3 ~} ~ ,~,3 ~3 ~,3 ~a ~a : ~
- .~. .. . .. . . . ,.. ; . . , .. ,, . . .. ~ . .. .... ............... ... .
~ . . ,, , ...,.. , ; . i. .-. -. . . .
21003~8 ~,c ~ ~ ~ o ~ o U. ' :' . ' ~ _ _ _ ,, ~,.'.-', oo~ l ) l ~ l u l ~ ~ l~n ' ' ' No _ _ N _ _ ~ 1:1 1~ l l i :? _ = _ _ = _ _ = _ _ ~ ,,,' .
~ o~ o o o~ = ~ r ~ r _ O N l l ~ .:, , ~ _ = Or~ Or _ r 3~ = or r ~ ~
J:~ ~ C qN ~ ol" C ~ O _rl ~
~ 0~ = ~ ~ ~ = S =
~ .r = . ~ 9~ ~k g~
~ _ _ _ . ' ¦ L~r ~a =a ~5 r ~ a ~a ~a ~a =a ~a ;~: -~ .
-:
210033$
~ C N O _ _ O ~O
. ~ _ _ oUo~ ~, U- V~ ~O U~ ~0 ~g g_ C_~ _l .~ ~_1(~ _ `D ~`1 O
8 ~ a o~ ~ ` ~ ' ~ :~ : ' a~
~ = 5 = :5: ~ = .-8" .
~ ~ ~ o~ o ~ ~ -~ ~ :, ~ ~ ~ ~ = ~ ~ .' ~ Orl O 8 ~ o ;
.! ~F~
r . = S
_ --8r'-o ~ = S ~ ' S =
~ ~ o ~ ~ 8 N ~ N 5~ N N
o a ~, l ~ , _ ~0~ ~0~ ~ 0~ _ ~
~ C~J-- ~ " ~ ~"N~ ~ ~ ~,~N
~ ~3 ~xi3 ~,,3 ~3 ~33 ~3 . '; ' ` ' ' ' ' ' 2-~6~8 To demonstrate the reduced intravenous to~icity, Sprague-Dawley rats of both sexes with a weight between 90 and 120 g were used, and which were administered the compounds via the caudal vein at a constant rate of 2.2ml/min (Salvesen S.
Acta Radiologica, Suppl. 362, page 73, 1980). After the injection, the animals were observed to record their immediate reactions and the respective mortalities were recorded during a period of seven days, followed by calculation of the lethal dose for 50% of the animals, LD50.
The most preferred compounds were studied, from Examples 9, 11 and 36, and they were compared with IOTROLAN as a reference which has already been mentioned. The physical~
chemical and toxicological data appear in the following table:
; . ,:: ., .:
.. .. .
- ,. . . . ,.. - - - . ~ ~ . . - ~ .- . - .. . .; .... . . . . .
210703~8 .
~ o ~ :~
~ ~q ~ ~ ~ :' --- ~ :
o~ ~ - - -- :
~3 ~ ~, N ~ N r~ ~ ~
E . j O H _ o e ~ _~ ~ _ :~ .
.
.
210Q~8 According to a preferred method, the compounds of -formula I are prepared by reacting a compound of formula II -. ~.
I ~ a II ;
R~ a with an acid chloride with the formula III --l8 R_~CN ~ ~ Cl III ;;~;
. . .: .
: . . :
in the presence of a basic catalyst, the radicals Rl to R8 having the signi~icance given previously.
During the reaction, the OH groups are protected as acetates or, when the OH groups are vicinal, as dioxepane. ~-~
These protective groups are easily eliminated by conventional ; 3c methods used in chemistry, such as hydrolysis.
The final compounds of general formula I are purified by treatment with ion-exchange resins, by conventional purification methods, or by means of preparative chromatoqraphy.
There follows a description of the preparation of ;~ ~ the preferred compounds mentioned in Table I.
.~ . .
. . . .
210l09338 Exam~le l N, N~ -bis-(2,3-dihydroxvmropyl)-N, N~ -dimethyl-5- ~ 3- ~N- ( 2,3-dihydroxy~ropyl)carbamoyll-5-methoxyacetamido-2,4,6-triiodo-S benzovlaminoacetamido~-2,4,6-triiodoisophthalamide (lCJ-1089) ~-a~ N- ~ 3 diacetoxvpropvl~-5-methoxyacetamido-2 4 6- ~ -triiodoisoohthalamovl ~ o~de.
Methcd I
To a solution of N-(2,3-diacetoxy-propyl)-~-amino-2,4,6-triiodoisophthalamoyl c.~loride (22.03g, 30 mmcl) in DMA (80 ml) cooled to 0-5 C, is slowly added a solution of methoxv2cetyl chloride (8 g, 90 Nmol) in DMA (20 ml). Once the addition has be~n completed, it is s~ --ad at room tempe-ature durin~ the night. The reaction medium is distributed between ethyl acetate (350ml) and wate (200 ml).
The 2aueous phase is ex~-acted with ethyl acet .e (3 x 50 ml) the or~anic extracts are combined and washed wl~:~ a 5~ sodium bicar~onate solution(2 x 50 ml) and a satura~ad solution cf sodium chloride (100ml). The product is dried cver anhydrous MgSO4 and the solvent is removed at reduced pressure. The product thus obtained is purified by recrystallisation from ethyl acetate (9O ml).
M.p.: 211/213 C. Yield: 62%
Method II
.
A mixture of methoxyacetic acid (3g.6 g, 0.4~ mol) and thionyl chloride (30.5 ml, 0.42 mol). is heated at 50 C ~or 35 two hours. It is cooled to room temperature and it is slowly add~d to a solution cooled to 0-~ C of N-( 2, 3 -diacPtoxy-propyl~-5-amino-2,4,6-triiodoisophthalamic acid (78.8 g, 0.11mol) in DMA (300 ml). Once the addition is concluded, it is stirred at room temperature until fully converted :
21~032g into N-(2,3-diacetoxypropyl)-5-methxyacetamidmid-2,4,6-triiodoisophthalamic acid (TLC with AcOEt/C~C13/AcOH 6:2:1) which is not isolated.
It is cooled aqain to 0-5 C and thionyl chloride ~32 ml, 0.44 mol) is slowly added, and stirring is maintalned for 30 minutes. The reaction medium is distributed bet-~een ethyl acetate (1120~1) and water (1060 ml). The aqueous phase is extracted with ethyl acetate (3 x 250ml) the organic extracts are combined and washed with sodium bicarbonate at 10~ (3 x 200 ml) and a satl~rated solution of sodium chloride (1 x 250ml). ~t is dried ove' anhydrous MqS04 and the solvent is removed at reduced pressure. The product thus cbtained is purifie~ by recrystallisation from ethyl acetate.
Yield: 75%.
b~ N N'-~is-(2~3-dihvdroxv~ro~vl~-~ N'-dimethvl-^-(3-rN-(2-3-dihvdroxv~ vl~carbamovl~-3-~ethcxvacetamido-2 4 6-triiodo-benzov~ noacetamido~-2 4,6-triiodoiso~hthalamide.
To a suspension o~ N,N'-bis-(2,3-dihvdroxy-propyl)-N,N'-dimethyl-~-aminoacetamido-2,4,6-t_iiodoisophthala~ide (3) (12 g, 0.015 mol) y and sodium carbonate decahydrate (13.1g, 0.046 mol) in DMA (60 ml), is added, with vigorous stirrin~, the compound previously described in example la) (13.5 g, 0.017 mol). It is stir_ed cont nuously at room te~perature until the ne~t day. It is filtP_ed, and the filtrate is concentrated to dryness at reduced pressure. The residue is dissolved in methanol/wate_ (1:1) y and is hydrolysed with 50% NaOH (pH 11.5) at 40 C. It is neutr~lised with concantrated hydrochloric acid (p~ 6.5) and evaporated to dryness at reduced pressure. The residue is dissolved in methanol and precipitated from isopropanol. Filte_ and dry in vacuo.
Yield: 70%.
The product obtained is purified by preparative liquid chromatography.
M.p.: 200 C (sinters)/ 230-257~C (deco~poses).
21~3~
Example 2 N N~-bis-(2 3-dihydroxypropylL-N~N~-dimethyl-5-(3-[N-~2~3-dihydroxypropyl~carbamoyll-5-hydroxyacetamido-2,4 6-triiodo-benzoylaminoacetamido)-2.4 6-triiodoisophthalamide (lCJ-1389 !
a) N-(2.3-diacetoxypropyl)-5-acetoxyacetamido-2.4.6-triiodo- -isophthalamoyl chloride Method I
To a solution of N-(2,3-diacetoxy-propyl)-5-amino-2,4,6-tri-iodoisophthalamoyl chloride (66.1g, o.O9o mol) in DMA (260 ml) cooled to 0-5 C, is slowly added acetoxyacetyl chloride (36.9g, 0.270 mol). Sitirring is maintained at room temperature until the next day. The reaction medium is distributed between ethyl acetate 400ml and water (800ml). It is extracted from the aqueous phase with ethyl acetate (3 x 250ml) and the combined organic extracts are washed with a 10% solution of sodium bicarbonate (2 x 200ml) and 10% sodium chloride (200ml). It is dried over anhydrous sodium sulphate and the solvent is removed under reduced pressure.
The product obtained is cold recrystallised from chloroform.
! Yield: 88-90% M.p.: 202-204 C
~etho~ II
To a solution of N-(2,3-diacetoxypropyl)-5-amino-2,4,6-triiodoisophthalamic acid (65.6g, 0.092 mol) in DMA (250 ml) cooled to 0-~C, is slowly added acetoxyacetyl chloride (50g, 0.366 mol). Stirring is maintained at room temperature for 3-4h., until it is totally transformed into N-(2,3-diacetoxy-propyl)-5-acetoxyacetamido)-2,4,6-triiodoisophthalamic acid, which is not isolated.
It is cooled to 5-10 C, and thionyl ~hloride (26.5 ml, 0.366 mol) is slowly added and maintained at this temperature for 45 minutes.
` 210~338 The product is isolated from the reaction medium in the same manner as in Method 1. Yield: 75%.
.
b) N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-S-(3-rN-(2,3-dihydroxypropyl)carbamoyl~-5-hydroxyacetamido -2,4,6-triiodobenzoylaminoacetamido)-2,4,6-triiodoisophthalamide.
Following the general procedure given in example lb) and starting from N,N'-bis(2,3-dihydroxy-propyl)-N,N'-dimethyl-5-aminoacetamido-2,4,6-triiodoisophthalamide (3) (20 g, 0.025 mol) and the compound described in example 2 a) (23.2 g, 0.028 mol). Gross yield: 70%. m.p.. 261-274 C (decomposes) ... ... .
Exam~le 3 N N'-~is-(l-hydroxymethyl-2 ! 3-dihvdroxy~ropvl)-s-(3rN-(2~3-dihvdroxy~rooyl)carbamoyll-5-hydroxyacetamido-2,4,6-triiodo-~enzovlaminoacetvl-N-methylamino1-2,4,6-tri1QdQiso~hthalamide. (lCJ-190 a) ~-c~loroacetyl-N-methylamino-2,4,6-triiodoiso~hthalovl chloride.
., '..
60 g (104.74 mmol) of 5-N-methylamino-2,4,6-triiodo isophthalic acid is suspended in 400 ml of ethyl acetate and S1.8 g (435.74 mmoles) of thionyl chloride are added. It is heated to maintain reflux for 4 hours. A solution of dichloride is :
obtained. Thin-layer chromatography is carried using to}uene-methanol (4:1) as an eluent. The product with an Rf=0.90 is observed. It is cooled to 60 C and 35.5 q (314.33 mmoles) chloroacetyl chloride is slowly added. It is , returned to reflux te~perature and heated f~r 7 hours.
After 1 hour, the desired product star~s to crystallise.
:' Thin-layer chromatography is carried out using toluene- -methanol (4:1) as an eluent, and the product with an Rf= 0.78 is observed.
The ethyl acetate is partially distilled off. -~
"'~ " ' . . .
21~0338 The product is cooled to room temperature and filtered off.
Obtained: 61g (molar yield: 84~).
b) N.N'-bis-(7-hydro~y=~,4-dimethyl- 3.5-d oxe~anyl~-5-chlo~oacetyl-N-methylamino -2.4 6-triiodois~p~thalamide.
185 g (269.59 mmol) of 5-chloroacetyl-N-methylamino-2,4,6-triiodoisophthaloyl chloride are suspended in 555 ml of dioxane. 169.7 g of sodium car~onate decahydrate (593.10 mmol) and 95.6 g of 2,2-di-methyl-;-hydroxy-6-amino-1,3 dioxepane (5~3.10 mmol) are added and heated to 50 C. After 8 hours total conversion to diamide occurs. Thin-layer chromatography is carried out using acetone-ethyl acetate (1:1) as an eluent, and a product with an Rf of 0.70 is observed. Salts are filtered off and the solvent is 1~ evaporated to dryness.
Obtained: 226 g (Molar yield: 90~) c~ N~N~-bis-(l-hYdroxymethyl-2 3-dihydroxyproDv1!-5-chloroacetyl-N-methvlamino-2.4.6-triiodoiso~hthalamide.
100 g of the compound from example 3b) are taken and dissolved in 300 ml of methanol. 3S% hydrochloric acid is added until a pH-l is reached, and the mixture is heated at 40-C until total hydrolysis is achieved with a quantitative yield, The product is evaporated to dryness.
Obtained: 91,4 g (quantitative3.
Thin-layer chromatography under the same conditions as in example 3b) retains the product totally at the origen. Using chloroform-methanol (3:2) as an eluent results in an Rf =0.57 d) N.N'-bis-(1-hydroxymethvl-2.3-dihydroxvpropvl)-5-amino-acetyl-N-methylamino-2 4 6-triiodoiso~hthalamide.
23.6 g of the compound of example 3c) (27.58 mmol) are dissolved in 27S ml of aqueous ammonia, and then heated at ~0-C for 24 hours. The product is evaporated to dryness.
The product is dissolved in methanol, the hydrochloride is formed and the solvent is removed.
..... . . . . ~ .. . . .. . . . . .
Thin-layer chromatoqraphy usin~ chloroform~-methanol (3:2~
as a eluent produces a stain at the origen. Using methanol as an eluent it produces a stain retained at R~=0.65. ~
Obtained: 12.5 g (molar yield: 54~) -e) N,N'-bis-(l-hydroxymethyl-2,3-dihydroxvproDyll-5-~3- ~N- :
(2~3-dihydroxypropyl)carbamovl]-5-hydroxyacetamido-2~4~6-triiodobenzoylaminoacetyl-N-methylamino~-2,4,6-triiodo-isophtalamide. (ICJ-290) '., 14 g (16.74 mmol) of the c~mpound from example 3d) is suspended in 60 ml of dimethylformamide, and 9.58~ (33.4a mmol) of sodium carbonate are added. The product is stirred for S min. and lS.1 g (18.08 mmol) of the produc~ from example 2a) are added. It is stirred at room temperature until the reaction is complete (24 hours).
......
The salts are filtered off, and the solvent which contains the dime- is evaporated to dryness. It is dlssolved in 100 -ml of methanol. It is then filtered and precipitated with 600 ml of isopropanol. It is filte~ed, drained and dried.
Crude product: 26 g (Yield: 95%).
The acetate grouos are hydrolvsed and the substance is puri~ied by preparative liquid c~romatography.
Pure produ~t: 12 g (molar yield: 48%).
Example 4 ,, N,N'-bis-L~h~droxvmethvl-~.3-dihvdro~_~ro~vl)-~-(3-~N-(2.3-, dihvdroxv~roovl~carbamovli-5-mç,thoxyacetamj~ ~-2~4 6- ::~
triiodoben~o laminoacetvl-~-met~v~ o~-2.4 6-triiodo-iso~hthalamide. ~lCJ- 290) -15.2 g (18.18mmol) of the compound from example 3d)is suspended in 70 ml of DMF, and 10.38 g (36.28 mmol)of -~
sodium carbonate decahydrate is added. The mixture is stirred for 5 ~in. and 15.8 g (19.59 mmol) of the compound from example la)is added. It is stirred at room tempe~ature ~-; 40 until the reaction is complete. (28 hours).
:
2fO~338 The salts are filtered off and the solvent is evaporated. The product is then dissolved in lO0 ml of methanol (inorganic salts are again filtered off) and it is precipitated in 600 ml of isopropanol. It is filtered off and dried.
Crude product: 27 g (Yield: 92%), The acetate groups are hydrolysed and the product is purified by preparative liquid chromatography.
Pure product: 13 g (molar yield: 47%).
Example 5 N.N'-~is-(2.3-dihydroxye~ro~vll-N.N'-dimethyl-5-~3-rN-tl-hydroxy~ethyl-2.3-dihydroxv~roovl~carbamo~11-5-methoxyace-tamidQ -2.4.6-triiodo~enzovlaminoacetamido~-2.~.6-triiodo-iso~hthalamide. flCJ -2489~
a) N-(4,4-dimethyl-7-hydroxy- 3,5-dioxepanyl)-5-methoxy-acetamido-2,4,6-triiodoisophthalamoyl chloride ~-To a cold solution of 5-methoxyacetamido-2,4,6-triiodo-isophthaloyl chloride (30.05 g, ~ mmol) in DMA (150 ml), a solution of 6-amino-2~2-dimethyl-l~3-dioxepane-5-ol (2) (7.98g 49.5 mmol) and triethylamine (4.55 g, 45 mmol) in DMA (30 ml) is slowly added. It is stirred for 2 hours and the reaction medium is distributed between ethyl acetate (400 ml) and water (500 ml). The aqueous phase is extracted with ethyl acetate (2 x 50~1) and the combined organic extracts are washed with a 5% solution of sodium bicarbonate (50ml) and saturated sodium chloride (50 ml). It is then dried over anhydrous magnesium sulphate and dried under reduced pressure. The product thus obtained is dried in vacuo.
Yield: 67% m.p.: 230-C (decomposes).
b ) N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-(3-~N-(l-hydroxymethyl-~,3-dihydroxypropyl)carbamoyl)-5-methoxy-acetamido -2,4,6-triiodobenzoylaminoacetamido)-2~4~6-triiodo- -isophthalamide, Following the general procedure described in example lb) and '$
starting from N,N'-bis(2,3-dihydroxy-propyl)-N,N'-dimethyl-S-aminoacetamido -2,4,6-triiodoisophthalamide (20 g, 0.025 mol) and the compound described in example Sa) (22.1 g, 0.088 mol), a partially-protected compound is obtained (Yield 73~) which is treated with hydrochloric acid diluted in methanol. The resulting product is purified by preparative liquid cromatography.
M.p.: 263-2~5 C. (decomposes) . .
Ex~m~Le 6 ~,N'-bis-(2.3-dihydroxy~ro~vlt-5-(3-rN-(1-hydroxvmethyl-2.3-dihydroxv~ro~yl!ca~a~oyll-5-methoxyacetamido-2,4 6-triiodo-benzoyla~L~oacetamidol-2.4.6-triiodoiso~hthalamide (lC~-20~21 '.; . ' 13.4 g ~47.8 ~mol) of sodium carbonate decahydrate are added to a solution of 11.9 g (15.6 mmol) of N,N'-bis-~2,3-dihydroxypropyl) -5-aminoacetamido -2,4,6- triiodoisophthal-amide in 60 ml of DMU. It is stirred vigorously for about 10 minutes and 14.8 g (18.7 mmol) of the compound described in example 5a) are then added. S.irring is continued during a whole night. The solid is filtered off and washed with methanol and the solvent is removed at reduced pressure. The residue is dissolved en 50 ml of methanol and the product precipitated with S00 ml of isopropanol. After filtering, the solid is washed with ethyl ether and dried in vacuo over phosphorus pentoxide, to obtain 18.8g of a sIightly coloured solid (81%). This solid is hydrolysed in a hydrochloric acid ~edium stirring at room temperature overnight. It is neutralised and the solvent is eliminated at reduced pressure. The residue is purified by preparative liquid chromatography. The fraction that contains the product is evaporated to dryness to obtain 10 g of product of with a chromatographic s~rength greater than 99~ with an m.p. >260-C
; 35 (which sinters at 254 C) .
Example 7 N.N'-bis-(1-hydroxy~thy1-2.3-dihvd~o~ypropy1t-5-~3-~N~
"' ` ' ' ' ~'' ' ' ~ ' . . . ' ", , -'!, . . . .. .
hydroxymethyl-2.3-dihydroxypropvl)carbamoyl1-5-methoxy-acetamido-2. 4 L 6-triiodobenzoylaminoacetamido~-2.4.6-triiodo isophthalamide. (lCJ-1889) a) N,N'-bis-(l-hydroxymethyl-2,3-dihydroxypropyl)-5-amino-acetamido -2,4,6-triiodoisophthalamide.
g (0.064 moles) of 5-phthaloylaminoacetamido-2,4,6-triiodoisophthaloyl chloride are dissolved in 200 ml of DMF.
40g (0.14 moles) of Na2C03.10H20 are added and cooled to between O and S C. 22.6 g (0.14 moles) of 5-amino-2,2-dimethyl-5-hydroxy-1,2-dioxepane dissolved in 50 ml of DMF
are then added and stirred at temperature room during 20 hours. Then, 12.44 ml (12.81 g, 0.28 moles) of hydrazine monohydrate are added and heated to 50-60 C for 8 hours.
The suspended solid is filtered off and the solution is evaporated to dryness. The residue is dissolved in 2N HCl and heated to 50 C for 10 minutes. The suspended solid is filtered off and the solution evaporated to dryness. The residue is precipitated from methanol/isopropanol. 41.2 g (78%) with a m.p. of 170-185 C is obtained.
b~ N N'-~is-fl-hydrQxvmet~yl-2,3-dihydroxy~o~vl~-5-(3-r N-(1-hy~o~ymLe~hvL-2,3-dihydro~y~ropvl~carbamovll-5-methoxi-acetami~Q=~,4,6-triiodobenzoylaminoacetamido~-2.~,6-triiodo-iso~hthalamide.
- ' . :
30.0 g (3.7g x 10-2moles) of the compound from example 5a) and 26 g (3.16 x 10-2moles) of the compound from example 7a) are di~solved in 168 ml of DMA. 27.1 g (9.48 x 10 2moles) of Na2C03.10H20 are added and stirred at temperature room for 20 hours. It is filtered and the solution evaporated to dryness. The residue is dissolved in methanol and precipitated with isopropanol. The crude product obtained is dissolved in methanol/water (1:1) and hydrolysed with 5% NaOH
at 45-50 C. It is neutralised and evaporated to dryness. The crude product ob~ained is precipitated from methanol/iso-propanol. 39g (yield:70%) was obtained with m.p. of 205-260 C
Exa~le ~ 2100338 N.N'-his-~l-hydroxymethvl-2.3-dihydroXypro~yl)-5-~3- ~-(2.3-dihydroxypropyl~carbamoyl~-5-hydroxyacetami~o -2,4.6-triiodobenzQ~ -methylaminoacetyl-N-methylaminol-2~4~6-tri iodo ~ . ~lCJ-390~
a) N N'-bis-(7-hydroxy-4,4-dimethyl- 3,5-dioxep~nyl)-5- : , methyl-aminoacetyl-N-methylamino-2.4,6-triiodolsooht~alamide.
~: , 180 g of the compound from example 3b) (192.37 mmol) are suspended in 1.450 ml of 30% methyl amine in ethanol are ;
warmed to 40'C for 30 hours, during which the transformation is completed. ~ -Methylamine is removed and it is then evaporated to dryness.
Obtained: 171 g (molar yield: 95%).
b~ N N'-bis-(1-hydroxymethvl-2 3-dihydroxvoro~vl)-~-methyl,-aminoacetvl-N-methylamino-2,4.6-triiodoisoohthalamide.
150 g (161.24 mmol) of the compound from example 8a) are dissolved in 500 ml de methanol. 35~ hydrochloric acid is added until a pH=l is reached. It is heated at 40 C until total hydrolysis has taken place. It is then neutralised with 50~ sodium hydroxide and the sodium chloride that is , formed is filtered o~. It is then evaporated to dryness.
Product obtained: 136.5 g (quantitative). -, Thin-layer cromatography under the same conditions as in example 3a) retains the product at the origen.
c) N.N'-bis-(l-hvd~oxymethyl-2.3-dihydroxypropvl)-S-(3-~N-~2.3-dihydroxyp~o~Ll~arbamoyl~-5-hydroxyacetamido -2,4.6-triiQ~s~gn~y~ methylaminoacetyl-N-methylamino)-2~4~6-tr -iodois~thala~ide.
18.7 g (22.0 mmol) of the compound from example 8b) aresuspended in 115ml of dimethylformamide, and 12.6 g of sodium carbonate decahydrate is added followed by 19.8 g (23.72 mmol) of the compound from example 2a). It is ~tirred at room temperature until the reaction is complete. (24 hours).
' ,' , ' `' ., ,., ,' ' ` ' ;
~ - 29 -210~338 The salts are filtered off and it is evaporated to dryness.
Then, the product is dissolved in lO0 ml of methanol and the salts again filtered off. It is precipitated with 600 ml of isopropanol. Crude product obtained: 33.7 g (Yield: 90%).
The acetate groups are hydrolysed and the product purified by ~ -perparative liquid chromatography.
Pure product obtained: 15 g (molar yield 45%).
Exam~le 9 . -:' .
N,N'-b~ -hyd~oxymethyl-2.3-dihvdroxvpro~yl~-5-(3-~N-(2.3-dihvdroxypropyl~carbamovl1-5-methoxvacetamido -2,~,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino)-2.4.6-tri-iodoiso~hthalamide. tlCJ-490~ ~
.-,,. .,:
18.l g (21.2g mmol) of the comDound from ëxample 8b) are - -dissolved in 80 ml of DMF, and 13.2 g (46.13 mmol) of sodium carbonate decahydrate are added. It is stirred for 5 min.
and 18,5 g (22.94 mmol) of the compound from example la) are added. It is stirred at room temperature until the reaction is complete. (24 hours).
The inorganic salts are filtered off and it is evaporated to dryness. The, it is then dissolved in lO0 ml of methanol, -filtered and precipitated with 600 ml of isopropanol. The product is then filtared off and dried.
Crude product obtained: 32 g (Yield 93~).
The acetate groups are hydrolysed and the product purified by preparative liquid chromatography.
Pure product obtained: 15 g (molar yield 46%) ,N'-bis~ hvdroxvmethyl-2,3-dihydroxy~ro~yl~-5- ~^~N- ~
35~ Ll~hydroxymethyl-~.3~di~v~c~v~rrovl~ bamoyl1-5-methoxy- -acetamido -2 4~6-triiodobenzoyl-N-methylaminoacetyl-N-~ethyl-aminot-2.4,6-~ o~oisophthalamide. ~ -690l 2}.9 g (25.76 mmol~ of the compound described in example 8b) are susPended ln lO0 ml of DMF, and 15.9 g (55.57 mmol) of sodium carbonate decahydrate are added. It is stirred for 5 minutes and 22 g (27.76 mmol) of the compound described in example Sa are added. Then, it is stirred at room temperature until the reaction is complete (30 hours). The -;
inorganic salts are filtered off and it is evaporated to dryness. The product is dissolved in 100 ml of methanol (salts are filtered off) and it is then precipitated with 600 ml of isopropanol. It is filtered off and dried.
Crude product obtained: 37 g (Yield: 90%) The acetonide compound is hydrolysed and purified by preparative liquid chromatography.
Pure product obtained: 18 g (molar yield: 45%) Exa~
N,N'~ is-(2.3-dihydroxyproovl~-5-13-rN-(2.3-dihvdroxv-~roovl)carbamovl~-S-hvdroxvacetamido-2.4.~-triiodo- -benzovl-N-methylaminoacetvl-N-methvL~mino~-2.4.6-triiodo-iso~hthalamide. (ICJ-1090~ -a) N N'-bis-f2.3-dihid~oxvpropvl~-chloroacetyl-N-methvl-amino-2,4.6-triiodoisoph~h~lamide.
120 g (0.17 moles) of the compound from example 3a) are suspended in 360 ml DMF. 99.3 g (0.34 moles) of Na2C03.10H20 are added and the mixture cooled to between 0 and S'C. A
solution of 30.7 g (0.34 moles ) of 3-amino-1,2-propanodiol in 90 ml of DMF is added and stirring is carried out for 20 hours . The solution is filtered and e~aporated to dryness. ;~
The residue is dissolved in methanoI and precipitated with ethyl ether.
12,5 g are obtained. (Yield: 94.3%). m.p.: 177-208 C.
b~ N.~'-bis-r~,3-d~ydroxy~opyll-5-methylaminoacetvl-N-methyl~in~o-2 4,6-triiodoisophthalami~e g (0,062 moles) of the compound in example lla) are dissolved in 350 ml of methylamine/ethanol at 33% and the solution stirred at room temperature for 3 days. The solution is evaporated to dryness and the residue : , ~ ,, . _ ,` , . .,: : , ,., , :. : . . :., ., . .. . . . , , .. . :
2 1 ~ ~-3 3 8 dissolved in methanol and precipitated with isopropyl alcohol.
Amount obtained: 33.3 g (Yield : 68%) m.p.: 178-205 C . , .
S c~ N.N'-~is-( 2.3-dihydroxypropyl)-5-~3- r N-t2.3-dihydroxy-~ro~yl)carbamoyl~-5-hydroxyacetamido-2.4.,6-triiodobenzoyl-N-methvlaminoacetyl]-N-methylamino~-2.4.6-triiodoiso-~hthalamide.
30 g (0.038 moles) of the compound from example llb) and 34.87 g (0.041 moles) of the compound from example 2a) ara dissolved in 190 ml of DMA. 32.61 g (0.11 moles) of Na2C03.10H20 are added and the mixture is stirred at room temperature for 20 hours. It is filtered, and the solution is evaporated to dryness . The residue is dissolved in methanol and precipitated with isopropanol. The crude product obtained is dissolved in methanol/water (1:1) and hydrolysed with 5% NaOH at 45-50 C. Then it is neutralised and evaporated to dryness. The crude product obtained (z 35 g) is purified by preparative liquid chromatography. Amount obtained: 20 g (Yield : 36.0%) m.p. : 256-268 C .
E~ElSLL2 N.N'-~L~-~2.3-dihydr~oxy~ropy~-5-~3-rNJ2.3-dihyd~Qx~-~ro~vl~ca~moyl]-5-met~oxyacetamid~,-2.4.6-triiodobenzovl -N-methvlami~oa~etyl_-N-methylamino)-2.4.6-triiodoisophthalamide.
(lCJ 1190) 22 g (0.027 moles) of the compound from example llb) and 24.71 g (0.030 moles) of the compound from example la) are dissolved in 140 ml of DMA. 23.74 q (0.083 moles) of Na2C03.10H20 are added and stirred at room temperature for 20 hours. After filterinq, the solution is evaporated to dryness. The residue is precipitated from methanol/
isopropanol. The product obtained (z 31.4 g) is dissolved in ~ethanol/water (1:1) and hydrolysed with 5% NaOH at 45-50 C.
,~ It is neutralised and evaporated to dryness. The crude product obtained (27.6 g) is purified by preparative liquid chromatography. Amount obtained: 14 g (Yield : 35.1 % ).
m.p.: 257-267~C .
2100338 :Example ~3 N N'-bis-f2.3-dihydroxyDropyl)-5-~3-~N-(2.3-dihVdroxyprOpyl~
carbamovll-5-hvdroxyacetamido-2.4 6-triiodobenzoyl-N-r2 3-S dihydroxypropyl~aminoacetamido)-2 4~6-triiodoisophthalamide.
(lCJ - 191) a) 5-chloroacetylamino-2 4.6-triiodoisophthaloyl chloride To a solution of 100 g (0.16~ mol) 5-amino-2,4,6-triiodo-isophthaloyl chloride in 300ml of DMA and cooled to 0-5 C, are slowly added 39.9 ml (0.502 mol) of chloroacetyl chloride. It is allowed to return to room temperature and is stirred for 6 hours. The reaction product is diluted with ~
700 ml of ethyl acetate and it is poured over lOOOml of water, -the organic phase is separated anc extracted with 2x150 ml of ethyl acetate. The combined organic phases are washed with 2x150 ml of saturated sodium bicarbonate solution and with 250 ml of 10~ sodium chloride solution. It is dried over anhydrous sodium sulphate, filtered and concentrated in vacuo until an abundant precipitate appears. After filtering it is washed with ethyl ether and dried ln vacuo. 95 g (84%) of the desired product are obtained.
Thin-film chromatography ttoluene) : R~ - 0.20 m.p.: 250-260-C (ethyl acetate) b) N.~ is-~2.3-dihydroxyproovl~-3-rN-(2.3-dihydroxvproDvl) amino~çetamidol-2.4.6-triiodoisophthalamide.
A mixture of 80 g (0.120 mol) of the product described in example 13aj, 119.2 g (0.416 mol) of sodium carbonate decahydrate and 76 g (0.834 mol)of 3-amino-1,2-propanodiol in 320 ml of DMF are heated to 50-60 C for 8 hours. It is filtered and concentrated in vacuo to dryness. The residue is dissolved in 240 ml of methanol, the salts that are precipitated are filtered off, and the product is precipitated in 2000 ml of isopropanol. It is filtered off and washed with ethyl ether.
-~338 The solid obtained is redissolVed in 400 ml of methanol and precipitated in 2000 ml of ethanol. After filtering, it is washed with ethyl ether and dried in vac~lo. In this way, 80 g (80~) of the desired product are obtained.
m.p. = 140-153-C
.. .
c) N N'-bis-~2.3-dihydroxypropyl~-5-(3- r N-(2.3-dihydroxy-proovl)carbamoyll-5-hydroxyacetamido-2.4.6-triiodobenzovl--N-(2.3-dihvdroxyproovl~aminoacetamido~-2.4.6-triiodo-iso~hthalamide. -"
Following the general procedure described example lb) and starting ~rom the compound described in example 13b) (30 g, 0.036 mol) and that described in example 2a) (29.9 g, 0.036 mol).
Yield crude product: 75%.
. , .
Examole 14 .
N.N'-bis-(2-hydroxyethvl)-5-/3- CN ~ 2.3-dihvdroxvoro~vl)-carbamoyll-5-hydroxyacetamido-2.4.6-triiodobenzoyl-N-(2, 3-dihydroxvetil~aminoacetamido~-2 4,6-triiodoisoohthalamide.
(lCJ-103) 2S Following the general procedure described in example lb) and starting fro~ N,N'-bis(2-hydroXyethyl)-5-[N-(2-hydroXyethyl)-aminoacetamido~-2,4-6-triiodoisophthalamide (described in DOS
292~417 ) (30 g, 0.040 mol) and the acid chloride described in example 2 aj.
~Yield of crudæ product:77%.
Example 15 : N ~ N ~ -~i s - ( 2 ~ 3~-dihyd~oxypropyl ~ -5- ~ 3 - r N- ( 2 ~ 3 -dihydroxv~ro~yl ) 35~ ~ carbamoyll~5-methoxyacetamido-2.4.6-~riiodobenzoyl-~ N-(2.3-dihydroxy~r~ inoacetamidol-2.4.6-triiodo-r ~ Q_b9~ ~ (lCJ-391) Followlng the general procedure described in example lb) and -starting from the compound described in example 13b) (30g, a :~
., . . . ' ... . . . .
~ 34 0.036 mol) and the acid c~ ~ scribed in example la) (28.9 g, 0.036 mol).
Example 16 S ' . :
N.N'-bis-r2-hvdroxyethyll-5-~3- r N-~2,3-dihydroxyoropvl)-carbamovll-5-hydroxyacetyl-N-(2-hvdroxvethyl)amino-2,4.6-tri-iodobenzovL-N-r2-hydroxyethvl)amino-acetvl-N-(2-hvdroxyethyll-amino)-2~6-triiodoisoohthalamide~ (lCJ-291) A mixture of the compound describe~ in example 14 (ICJ-103) (23 g, 0.016 mol), trisodium phosphate dodecahydrate (32.4 g, 0.085 mol) and 2-chloroethanol (4.6 ml, 5.48 g, 0.068 mol) in methanol (60 ml), are refluxed for 2 to 3 days.
The crude product of the reaction is filtered, evaporated to dryness at reduced pressure, and the residue is purified by ~-preparative liquid chromatography.
Yield: 5~S m.p.: 215-238-C (decomposes) .-ExampLe 17 :.
N~N~-bis-(2-hydroxyethyll-5-~3-rN-!2~3-dihydroxvoroovl)-.. . .
carbamovll-~-methoxvacetamido-2.4,6-triodobenzovl-N-(2-25 hvdroxyethvllaminoacetamido~-2.4.6-triiodoiso~hthalamide.
(lCJ-105) Following the general procedure described in example lb) and starting from N,N'-bis(2-hydroxyethyl)-5-~N-(2-hydroxyethyl)-aminoacetamido)-2,4,6-triiodoisophthalamide described in DOS
2928417 (30 g, 0.040 mol) and the acid chloride described in -~1 example la) (32.4 g, 0.040 mol).
. Yield of crude product: 80%. -~
Example 18 N~N~-bis-(2~3-dihyd~oxypropyl)-5-~3-rN-(2~3 carbamoyll-5-hydroxyacetamidol-2.4,6-triiodobenzoylamino-acstamido)-2.4.6-triiodoisophthalamide. (lCJ-790) ', .
210~3~8 :
Following the general procedure described in example 1 b) and starting from N,N'-bis(2,3-dihydroxy-propyl)-5-amino-acet-amido-2,4,6-triiodoisophthalamide (20g, 0.026 mol) and the acid chloride described in example 2a) (26.3 g, 0.031 mol).
In this case, the crude is purified by recrystallisation in s water.
Yield: 76% m.p.: 230-270 (decomposes) Example 19 N,~'-bi~-(L-hydroxv~ethyl-2.3-dihvd~QxvprQpvl)-5-l3-[N- -(2,3-di~ydroxYpropvl~carbamoyll-5-hy~oxyacetamido-2,4.6-triiodobenzovlaminoacetamidot-2.4.6-triiodoisoohthalamide.
(lCJ-158g) 1 5 . : . ., 28.0 g (3.3xlO 2moles ) of N-(2,3-diacetoxypropyl)-5-acetoxy-acetamido-2,~,6-triiodoisophthalamoyl chloride, described in example 2a) and 23.0 g (28xlO 2 moles) of the compound described in example ~a) are dissolved in 150 ml of DMA.
20.8 g (7.26xlO moles) of Na2C03.10H20 are added and stirred at room temperature for 20 hours. The salts are filtered off and the solution evaporated to dryness. The residue is -dissolved in methanol and precipitated in isopropanol. The product obtained (34.0 g) is dissolved in water/ methanol (1:1) and hydrolysed with 5% NaOH. It is neutralised and evaporated to dryness. The crude product obtained is~; !:' " ' precipitated in methanol/isopropanol. 27.5 g were obtained (Yield: 65.7~) m.p.: 200-255-C.
Exam~le 20 . ~
N.N'~ hyd~ xymethyl-2.3-dihydroxypropyl~-S-~3-rN-(2.3-dihvdroxypropy~carbamoyl]-5-methoxyacetamido-2.4 6-triiodobenæoylaminoacetamido)-2.4.6-triiodoisolphthalamide.
(lCJ-168s) ---~'~: : . .
23.5 g (0.02g moles) N-(2~3-diacetoxypropyl-2~4~6-triiodo--.:
._~ ... .. .
isophthalamoyl chloride, desc~i~Q~ ~n3~xample la) and 20.0 g (0.043moles) o~ the compound described in e~ample 7a) are dissolved in 110 ml oS DMA . 20.8 g (O.072 moles) of Na2C~ OH20 are addec and s.ir~ed at room temperature for 2~
hours. The salts in suspensicn are filte-ed Off and the solution is evaporated to dryness. The resicue is dissolved in met~anol and precipitated in isopropanol. The produc_ -obtained (40 g) is dissolved i~ methanol/wz.ar (1:1) znd hydrolyseA with 5% NaO~ a- 4 -~0 C. The product is neut-al seA an~ evapcrated t~ c-yness. The c~ude prcduc-obta-'ned is pre~ipita'e~ in meth2~cl/isopropa..cl. 28.7 g cr produc_ is obtained (78.4~). m.~.: 200-280 C.
Exam~le 2.1 N~N~-~ls~ hv~~~xvme',~L;z~ x~r~cv~-^-i 3 - r N- ( 2 .: -dihvd~ vl~carbamov~ -me_:-xy2ce~amidc-:.4.6-t-lioc~
benzov'-~ ethvlamino2c~tamido~ 6-t~~iodc-se-nt~zlam-ce.
(ICJ-1~91) :.
' ' a) N,~'^b~s-(l-hvdrcxvmethvl-2, -d hvdroxv~roc~ methv'-aminoacs~2mido-2,4,6-t--iodoiso~ a21amide.
? 5 Following t~e procedura used in ex2mple 24b) and s~ar~ nc ~rom from 40 g (40.3 mmol) c~ N~N~-bis-(/-hidroxv-al4-dimethyl-3,_-dioxepanyl)-5-chlcr~zc_tamido-2,4,0-triiodo-ls -pht.~a}amide, (example 22a), and ~v means of the cor-esponc na acid hydrolysis at 40 C, a syr-pv residue is obt~ined wh-ch is precipi-~ted by means of me-~anol-isopro~anol. AL~e_ filteri~a and dryina with P20g, ~.3 S (~8%) o~ a slightlv coloured solid is obtained. ' '' b~ -bis-~1-hvdroxv~ethvl-2.3-d hvdroxv~ro~vl~-5-t3-r~ , 2 3-dihvdroxy~roovllçar~amovL ~ ethoxvacetam d~-2.4.6-triicdoben20vl-~-~ethvlamincacstamido)-2 ~.6-t-i-iodoisophth~amide.
-~ suspension of 2S a (29.9 ~mol) of U~N~-~is-(l-hydr methyl-2~3-dihydroxypropyl)-5-methylaminoacet~mido-2~4~6-.
-æ~0~33s triiodoisophthalamide, (previous example) is stirred at room temperature for 10 hours with 24.1 g (29.9 mmol) N-(2,3-diacetoxypropyl)-5-methoxyacetamido-2,4,6-triiodoiso-phthal-amoyl chloride, (example la) and 17,1 g (59.8 mmol) of sodium5 carbonate decahydrate in 200 ml of DMA. It is filtered and the solvent removed under reduced pressure. The residue is dissolved in methanol and precipitated from isopropanol.
The product is filtered and dried in vacuo, to obtain 62 g of a slightly coloured product. This solid is hydrolysed in an a~ueous alcoholic solution with 20~ NaOH. It is neutralised with 20% HCl and the solvent is removed under reduced pressure. The residue is dissolved in methanol and precipitated from i~opropanol. It is filtered and dried in vacuo to obtain 34 g (75%) of a slightly coloured solid which is purified by preparative liquid chromatography.
. .: -. -~ .
Exa~nl~
..
20 N~N~-bis-(l-hydroxvmethvl-2~3-dihvdroxvpro~vl~-5-l3-rN-~2~3~
dihydrqxy~opvllcarbamovl~-5-methoxyacetamido-2 a 6-triiodo-benzovl-N-L~-~yd~o~yethyl)aminoacetamido~-2.4.6-t-iiodo-iso~hthalami~de~ (lCJ-16~1) -25 a~ N,N -bis-(4.4-dimethvl-7-hydroxy- 3.5-dioxepanvl~-5-chloro-acetamido -2.4.6-triiodoiso~thalamide.
A suspension of S-chloroacetamido-2,4,6-triiodoisophthaloyl chloride (134 g, 0.2 mol) described in example 13a), sodium 30 carbonate decahydrate (172 g, 0.6 mol) and 6-amino-2,2-dimethyl-1,3-dioxepane-5-Ql (32g, 0.2 mol) are heated to 55 C - --for 12-24 hours in acetone (400 ml). The solvent is removed in vacuo and the residue crushed with water. It is filtered of~ and dried in vacuo. Yield: 52%.
b~ N.N -bisLl-hydroxymethvl-2.3-dihydroxy~ropyl~-5-rN-2-hydroxyethyl)aminoacetamidol-2.4.6-triiodoiso~hthalamide.
A suspension of the compound (50g, 0.54 mol) as obtained in ;~ -: :
~ :., .
., ~, . ~.. .... . .. . . . . ... . .~ .... .... .. . .. . . . . . .
2100~
the previous section a), and 2-aminoethanol (8.1 ml, 7.98 g, 0.131 mol) is heated in ethanol (200 ml) at 50'C for 3 days.
When the transformation into N,N'-bis-(4,4-dimethyl-7-hydroxy-3~5-dioxepanyl)-s-[N-(2-hydroxyethyl)aminoacetamido]-2,4,6-triiodoisophthalamide - which is not isolated - is complete, the reaction medium is diluted with ethanol (200 ml) and hydrolysed by acidulating with hydrochloric acid.
It is evaporated to dryness at reduced pressure and the residue is dissolved in methanol and precipitated in isopropanol. Filter and dry in V2C'10.
Yield: 73%.
: '.
c) N L~ -bis-(1-hvdroxy~ethvl-2,3-~ihvdroxv~roovl~-5-~3- rN-~ -1~ (2,3-dihydroxypropvl)carbamov' -5-methoxvacetamido-2.~ 6- -triio~obenzovl-N-~2-~vdroxvethvl~aminoacetamido~-2.4 6-triiQ~o-iso~hthala,m~,de,. : ~ "
Following the general procedure described in example lb) and starting ~rom the compound descr ~ed in the previous section b) (23 g, 0.027 mol) and with t:~e acid chloride in example la) t21.41 g, 0.027 mol). -Yield of crude product: 70%.
'' ~
: : ' :
, ~ ~ ; - , ,, -2l0a33s N~Nr-bis-~2~3-dihydroxy~ro~vl~-5-~3-rN-(2-~3-hvdrcxvpro~vl~ :
car~amovll-s-acetamido-2.4 6-triiodobenzovl-N-(2.3-dihydroxv-Pro~vl)aminoacetvl-N-methvlamino~-2.~6-triiodoisophthalamide.
(lCJ - 1891) a) N,N'-bis-(2,3-dihydroxypropvl)-5-i3-~N-(2,3-dihydroxypropvl) -aminoacetyl-N-methvlamino~-2,4,6-triiodoisophthalamide.
1 0 ~ ' This is prepared following the pr~cedure desc-ibed in Example 13b), and starting f~om 5-c~lorvacety7-N-methylam1no-2,4,6-triiodo-~sophthaloyl chloride des~~ibed in Example 3 (82.3 g, 0.12~ mol), sodium carbonate decahvdrata (120.1 ~, 0.420 mol) and 3-amino-1,2-propanodiol (54.6 c, 0.600 mol).
Yie7d: 78%.
b) N,N'-_is-(2,3-dihydroxypropyl)-_-~3-~N-(2,3-dihydr~xy-prooyl)carbamoyl]-5-acetamido-,~,4,6-t~iiodcoenzoyl-N-(2,3-dihydroxypropyl)aminoacetyl-N-~e~hylamino-2,4,6-t-iiodo- -~
isophthalamide.
Followina the general procedure des~ribed in Example lb) and star~ing rom the compound descr,_ed in the pravious section -~
a) (40 g, 0.047 mol) and t~e ch ~ride of t;~e acid described in Example 36~) (36.53 g, 0.047 moi).
Yield: 76%.
E~AMPLE 44 . ~
N N'-~is-~,3-dihvdroxv~ro~vl)-N.N'-dimethvl~ 3-rN-(2,3-dihvd~oxv~r~vl~car~amovll-~-nvdr~xvacet~mido-' ~,6-t-llodo- 7 benzov~-N-~ethylaminoa~tvl-N-methvlamino~-triiodo-iso~thalamide. (lCJ - 890) a) N,N'-~is-(2,3-dihydroxypropyl)-~,N'-dimethyl-5-chloroacetyl-methylamino-2,4,6-~~iiodoisophthalamide.
118 g (0.77 moles) 5-chloroacetyl-N-methylamino-2,4,6-triiodoisophthaloyl chloride are suspended in 240 ml of DMF.
97.28 g t-74 moles) of Na2C03.10H20 are added and the solution cooled to between 0 and 5 C.
. ~ .
.: .
- 4o2l~o3~8 Once this temperature has been reached, 39.7 g (0.34 moles) of N-methyl-3-aminopropano-diol is added dropwise, dissolved in 65 ml of DMF. Once the addition has been ended, it is allowed to return to room temperature and it is stirred for hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The resulting residue is dissolved in 200 ml of methanol and precipitated by addition into one litre of ethyl ether. The solid that is precipitated is filtered off, washed with ether and dried in vacuo. 131.2 g are obtained.
(Yield: 93.7~). m.p.: 130-165C.
b) N,N'-bis-(2,3-dihydroxypropyl) N,N'-dimethyl-5-methyl-aminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide A solution of 70g (25 mmol) of N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-chloroacetyl-N-mezilamino-2,4,5-triiodo-isophthal~amide and 70 ml of 33% alcoholic methylamine in 140 ml of ethanol is heated at 40 C fo 30 hours. It is cooled to room temperature and filtered. The solvent is removed under reduced pressure. The residue is dissolved in 100 ml of methanol and this is added to 200 ml isopropyl alcohol. once the addition has been finished, it is stirred for a few minutes and filtered. The solid is washed with isopropyl alcohol and ethyl ether, and then dried in vacuo over P2O5. 41.9 g (52%) of a colourles ~olid is obtained.
c) N,N'-bis-(2,3-dihydroxylpropyl)-N,N'-dimethyl-5-~3-[N-2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylamino acetyl-N-methylamino)-triiodoisophthalamide To a solution of 2.3g (26 mmol) of N,~'-bis-(2,3-dihydroxy-propyl)-N,N'-dimethyl-5-methylaminoacetyl- methylamino-2,4,6-triiodoisophthalamide in 270 ml of DMA are added 22.3 g (78 ) of Na2CO3.10H2o There is then added 22.7 g, (28.6 m~ol) of the chloride described in Example 2a), the mixture is stirred at room temperature until the following day and it is evaporated to dryness at reduced pressure (weight of the residue: 50.2 g).
The residue is dissolved in 1:1 aqueous methanol and is hydrolysed with 5% NaOH at 40 C. It is cooled to room temperature and neutralised with 20% HCl. The solvent is removed at reduced pressure and 100 ml of methanol is added to the residue. The methanol solution is added to 1000 ml of isopropyl alcohol. Once the addition has been ended, it is stirred for a few minutes and filtered. The product is dried in vacuo over P2O5, and purified by preparative liquid chromatography.
. .
N,N'-pis-(2,3-dihydroxypropyl~-N.N'-dimethyl-5-13-~N-(2~1,3,,-d -hydroxypropyl)carbamoyl~-5-methoxyacetamido-2~4~6-triiodo-benzoyl-N-methylaminoacetyl-N-methylamino)-2 4 6-triiodo- :
iso~hthalamide (lCJ - 990) ;
To a solution of 21.3 g (26 mmol) of the compound from example 24b) in 270 ml of DMA, is added 22.3 g (78 mmol) of Na2CO3.10H2O and 23.06 g (28.6 mmol) of the compound from Example la). It is stirred at room temperature overnight.
It is filtered and evaporated to dryness at reduced pressure.
(weight oE the residue 51.2 g). ~
,:. ''. :
~he residue is dissolved in 50% aqueous methanol and hydrolysed at 40'C with 20% NaOH. It is cooled to room temperature and neutralised with 20~ HCl. The solvent is removed at reduced pres8ure and the residue treated with 100 ml of methanol. The methanolic solution is precipitated with 1000 ml of isopropyl alcohol. After stirring for 5 minutes it is filtered, then dried in vacuo and filtered off, followed by drying in vacuo over P2O5. 30 g of a slightly coloured solid are obtained which is purified by preparative liquid chromatography. 19.9 g (51%) of a colourles solid is obtained.
. ~ . .
EXAM~LE 26 ~ -N.N'-bis-r2.3-dihydroxypropyl~-N.N'-dimethyl-5-~3-rN-~2.3-ihvdroxypropyl)carbamoyll-5-hydroxyacetamido-2.4.~-triiodo-ben~oy~aminoacetyl-N-methylamino~-2,4,6-triiodoiso-phthalamide ~lCJ - 1290) 20 g (0.023 moles) of the compound from Example 2a) and S ' ~ ?, ~
17.51 g (0.021 moles) of N,N'-bis-~2,~-dihydroxypropyl)-N,N'-dimethyl-5-aminoacetyl-N-methylamino-2,4,6-triiodoiso-phthalamide are dissolved in 112 ml of DMA. 18.12 tO. 06amoles) Na2C03.10H20 are added and it is lef~ to stir at ro~m temper~ture for 20 hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated in isopropanol.
The product ootained (x 24 g ls dissolved in methanol/water (1:1) and hydrolysed with 5% NaOH at 45-_0 C. It is neutralised and evaporated to dryness. The crude produc-obtained is purifie~ by preparative liquid chromatographv.13.2 g. is obtained.
(Yield: 41.2 %) m.p.: 110 - 210-C.
EXAMP~ 2, N,N'-bis-(2,3-dihydroxvpropylj-~,N'-dimethvl-~-~3 rN-(2,3-dihydroxypropyl)carbamoyl¦-methoxyacetamido-2,4,6- -triiodobenzoylaminoacetvl-N-methylamino~-2,4,6-triiodo-iso~hthalamide (lCJ - 1390) 19.3 g (0.024 moles) of the c~mpound from example la) and 17.5 g (0.021 moles) of the compound described in DOS 2 928 417 are dissolved in 112 ~1 of DMA. 18.3 a (O.06~ moles) o~
Na2C03.10H20 are added and stir.ed at room temperature for 20 hours. The insoluble sal~s are filtered off and the solution evaporated to dryness. The product obt~ined (z 27 g) is dissol~ed in (1:1) water/methanol and hydrolysed with 5%
NaOH at 45-30 C. It is neut~alised and evaporated to dryness. The crude product is purified by preparative liquid chromatography. 14.5 g. are obtained. (Yield: 44.Q~) m.p. Sinters and decomposes betwe~n 140 y 230 C.
t-bis~ 3-dihvdrox~2ropvl~-5-(~-rN-(2~3-dihvdroxv~r car~amoyll 5-~ethoxyacetamado-2 4 6-t~LL~lS~æL~9&l~in acetyl-N-methvlamino)-2 4~6-triiodoiso~hthalamide.
(lCJ - 1590) ~ . . . . .. . .. ... .. . . . .. ... .
210~33~
a) N~N~-bis-(2t3-dihydroxypropyl)-5-aminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide -50 g (0.062 moles) of 5-phthaloylamino-acetyl-N-methylamino-2,4,6-triiodoisophthaloyl chloride are dissolved in 150 ml of DMF. The mixture is cooled to between 0 y 5-C and 36.48g of :
Na2C03.10H20 (0.124 moles) and 11.4 g (0.124 moles) of 3-amino-1,2-propanodiol dissolved im 50 ml of DMF, are added.
It is left stirring at room temperature for 24 hours. 12 ml (0.25 moles) of hydrazine hydrate are added. The mixture is heated to 50-C for 3 hours. The suspended solid is filtered off and the solution evaporated to dryness. The residue is dissolved in 2N HCl and heated at 50-C for 10 minutes. The suspended solid is filtered off and the solution evaporated to dryness. The residue is precipitated from methanol/
isopropanol. 24.0 g are obtained.
(Yield: 50S). m.p.: 220-230-C.
b) N,N'-bis-(2,3-dihydroxypropyl)-5-(3-tN-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl- - -aminoacetyl-N-methylamino -2,4,6-triiodoisoDhthalamide . .
. ' -21.72 g (0.027 moles) of the compound described in Example -;
la) and 19.0 g (0.024 moles) of N,N'-bis-(2,3-dihydroxy-propyl)-5-aminoacetyl-N-methylamino-2,4,6-triiodoisophthal-amide are dissolved in 122 ml of DMA. 21.03 g (0.073 moles) of Na2C03.10H20 are added, and stirred at room temperature for 20 hours. The insoluble salts are filtered off and the solution evaporated to dryness. The residue is dissolved in methanol and precipitated in isopropyl [alcohol]. The product obtained~ (~ 32 g ) is dissolved in (1:1) methanol/water and hydrolysed with 5% NaOH at 45-50-C. The solution is neutralised and evaporated to dryness. The residue is recrystallised from water. 14.4 g. of product is 3S obtained. (Yield : 40.2 % ). m.p.: Sinters and decomposes between 130-210-C.
N.~ N~N~-tetraki~-(~-hydrox~ethyl~-5-f3- r N-(2~3-dihydroxyprs~LL
- 44 ~ 21 0 ~3~ 8 carbamQvll-5-hydroxyacetamido-2~4~6-triiodobenzoyl-N-methyl~
aminoacetyl-N-methyl~mLnQ~-~.4 6-triiodoiso~hthalami~dç (lCJ-1690) a) 5-chloroacetylmethylamino-N,N,N',N'-tetrakis-(2-hydroxy-ethyl)-2,4,6-triiodoisophthalamide ~ --To a solution of 27.5 g (40 mmol) of the compound in Example ~-3a) in 85 ml of DMF is added 22.9 se anaden 22.9 g (80 mmol) f Na2C3 lH2 It is cooled to 10 C and to it is added a solution of 8.83 g ~84 mmol) of diethanolamine dissolved in 8 -11 ml of DHF. Once the addition is completed, it is warmed to ambient temperature for three hours and the solvent is removed undèr reduced pressure to obtain a solid residue (16 g). The residue is dissolved in MeOH and 500 ml of ethyl ether are added. Once the addition is complete, it is `
stirred for a moment and filtered, and dried in vacuo over ~ -P2O5. 28 g of a slightly coloured solid are obtained which is purified by c.c. flash (acetone/MeOH 2:1). 19.6 g (60%) ~-of a colourless solid are obtained with a m.p. of 60-98 C.
: ' :, b) 5-methylaminoacetyl-N-methylamino-N,N,N',N'-tetrakis-(2--hydroxyethyl)-2,4,6-triiodoisophthalamide , .; .
A suspension of 70 g (85 mmol) of the compound in Example -29a) in 140 ml of ethanol and 70 ml of a 33% methylamine in ethanol solution are stirred together at 40-C for 30 hours.
It is filtered and evaporated to dryness. The residue is dissolved in 120 ml of methanol and it is added to 900 ml of isopropyl alcohol. When the addition has ended , it is filtered and dried in vacuo over P2O5. 21.8 g of a colour- -less solid is obtained which is purified by flash c.c.
(CHCl3~Me0H 3:2). 15.1 g (22%) of a colourless solid is obtained.
c) N,N,N',N'-tetrakis-(2-hydroxyethyl)-5-~3-[N-~2,3-dihidroxy--propyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~-2,4,6-triiodo-isophthalamide To a soIution of 21.~3 g (26 mmol) of the compound of Example 29b) in 270 ml of DMA is added 22.3 (~8 mmol) Na2C03.10H2O
and 22.7 g ~28.6 mmol) of the compound of Example 2a).
_ 4521 003~8 It is stirred at room temperature overnight and filtered at reduced pressure (weight of residue: 52.3 g.). ~
The residue is dissolved in 50% aqueous methanol. It is then -, hydrolysed at 40 c with 20% NaOH, cooled to room temperature and neutralised with 20% HCl. The solvent is removed under -reduced pressure and the residue is treated with 200 ml of methanol. The methanol solution is precipitated in 1000 ml of isopropyl alcohol. It is filtered off and dried in vacuo with P205 to obtain 34.6 g of a yellowish solid which is purified by preparative liquid chromatography. 16.6 t43%) of a colourless solid is obtained.
N.N,N'.N',l'-tetrakis-f2-hydroxyethyl ! - 5-(3-~N-(2.3-dihydroxy- ~-~ropyl~carbamoyll-5-methoxyacetamido-2.4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino -2.4.6-triiodo-isophthalamide (lCJ - 1790) To a solution of 17 g (20.8 mmol) of the compound from Example 29b) in 215 ml of DMA, are added 17.85 g (62.4 mmol) Na2C03.10H20 and 18.5 g (22.9 mmol) of the compound from Example lal, and the whole is stirred at room temperature for a night. It is filtered and evaporated to dryness under reduced pressure (weight of the residue 29 g.) .
The residue is dissolved in 50% aqueous methanol, and hydrolysed at 40 C with 20% NaOH. It is cooled to room temperature and neutralised with 20% HCl. The solvent is removed under reduced pressure. The residue is treated with methanol and the methanol solution is precipitated with isopropyl alcohol. Once the precipitation has finished, it is stirred for a moment, the product is filtered off and dried in vacuo over P205. 23.7 g of a slightly coloured solid is obtained which is purified by preparative liquid chromatography.
15.6 g (50~) of a colourless solid is obtained.
~1~03~8 ~-EXAMPLE 3l N.N.N'.N'-tetrakis(2-hydroxyethyl~-5-~3-~N(2.3-dihydroxv-~ropyl)carbamoyll-5-methoxvacetamido-2.4.6-triiodQbenzoyl-aminoacetamido)-2,4~ 6-triiodoisophthalamide (lC~ - 1890) a) 5-phthalimidoylacetamido-N,N,N',N'-tetra-kis-(2-hydroxy-ethyl)-2,4,6-triiodoisophthalamide - -To a solution of 31.3 g (40 mmol) of S-phthalimidoylacet-amido-2,4,6-triiodoisophthaloyl chloride in 85 ml of DMF is added 22.9 g (80 mmol) of Na2C03.lOH20. It is cooled t~
lO C and 8.83 g (84 mmol) of diethanolamine in 8 ml of DMF
are added. once the addition has been completed, it is warmed to room temperature and stirred overnight. It ls lS filtered and evaporated to dryness at a reduced pressure.
Finally, it is broken up in 50 ml of water. It is filte~e~ -off and dried in vacuo ove~ P205, to obtain 20.2 (55%) o~ a colourless solid.
b) 5-aminoacetamido-N,N,N',N'-tet-akis-(2-hydroxyethyl)-2,4,6-triiodoisophthalamide A suspension of 60 (65.2 mmol) of the compound from Example 31a) in 210 ml of ethanol is refluxed, and 13.05 g (260.8 mmol) of NH2-NH2.H20 are added, the product of the reaction redissolving a~ter a few minutes. After 7 hours, it is cooled to room temperature and the solvent is removed unde_ reduced pressure from the reaction medium. The residue is stirred at 40-C with 250 ml of 5% ~Cl for one hour. It is cooled to room temperature and filtered. The filtrate is evaporated to dryness under reduced pressure. 50 ml of MeO~
are added and it is then left in the refrigerator overnight.
The hydrazine hydrochloride is filtered off and the filtrate is concentrated to 2/3 of its initial volume, and it is again left in the refrigerator overnight. The product is filtered o~f and washed with methanol (l x lO ml) and ethyl ether ~l x lO ml) and dried in vacuo over P205. 18.l g (74%) of a colourless solid is obtained.
c) N,N,N',N'-tetrakis-(2-hydrOxyethyl)-5-~3-[N-(2~3-dihydroxy- --propyl)carbamoyll-5-methoxyacetamido-2,4,6-triiodo-benzoyl- --3 3 ,~
aminoacet~mido~-2,4,6-triiodoisophthalamide.
To a solution of 20 g (25.3 ~mol) of the co~pound from E~ample 31c) in 200 ml of DMA are added 21.7 (75.9 ~mol) Na2C03.lOH20 and 22.5 g (27.8 mmol) of the compound from Example la). It is stirred at room temperature overnight.
It is filtered and the solvent removed under reduced pressure (weight of residue S2 g).
The r~sidue is dissol~ed in 200 ml of 50~ aqueous met~anol and hydrolysed with 20S NaOH al 40 C. I; is cooled to room témperature and neutralised with 20% HCl. The solvent is removed under red~ced pressure. The residue is purified by rec-ys~allisation (MeOH/H20) to obtain 24.1 g (63%) of a .
colourless solid.
lg : .
EX~p~,~ 32 ~ ~ -N, N ~ -bis-~2-hvdroxvethvl~ 3-rN-~2~3-dihvdroxvor carbamcv~ -methoxv~cetyl-~-(2-hvdroxvethvl~amino-2.4 6-t~iiodobenzovl-N-(2-hvdroxvethvl~a~inoacetv~ 2-hvdroxvethvl`-amino~-2 4 6-triiodoisoohtha}amide (lCJ - 491) Followin~ the general described for the compound of Example 2~ 16) and startin~ ~rom: 30 g (O.OZl mol) of the compound from Example 17, 42.3 g (0.111 mol) t~isodium phosphate dodeca-hydrate and 6.0 ml (7.2 g, 0.08~ mol) of 2-chloroethanol.
Yield: 45% m.p.: 220 -240-C
EXAMPLE 3~
N.N'-bis-(2,3-dihydroxy~roovll-5-~3-rN-t2,3-dihydroxv~roovl)-carbamovll-~-methoxyacetyl-N-(2-hvdrqxyethvl~amin~-~ 4 6-tri-3 5 ~ iodobenzoyl -N- ( 2-hydroxyethyl ) amLnoacetyl-~-( 2-hy~roxye~hyl ~ - . . amino)-2 4.6-triiodoisophthalamide ~ (lCJ - 631) '~ ~ ' : :
0 3 ~
a) N,N'-bis-~2,3-diacetoxypropyl)-5-chloroacetamido-2,4,6-triiodoisophthalamide To a solution of 87.3 g (0.1 mol) of 5-amino-N,N-bis-(2,3-diacetoxypropyl)-2,4,6-triiodo-isophthalamide in 260 ml of DMA, cooled to between 0-5 C, is slowly added 23.9 ml (33.9 g, 0.3 mol) acetoxyacetyl chloride. It is allowed to return to room temperature and is stirred for 5 - 6 hours. - -~
9 ml of water are added to des~roy the excess of acid chloride and it is poured into 1,250 ml of cold water. The water is decanted off and the grease that is formed is ' '' dissolved in 450 ml ethyl acetate. The water is extracted with 3 x 350 ml of AcOEt. The combined organic extracts are '' washed with : a) 2 x 250 ml 10% sodium bicarbonate solution ~' and b) 250 ml of a 10% sodium chloride solution. It is dried ' ' over anhydrous magnesium sulphate, filtered and the solvent ' removed under reduced pressure. The solid obtained is dried in vac~o.
Yield: 95 - 99% ~ ' m.p.: 190-205-C. ' "
b) N,N'-bis-(2,3-dihydroxypropyl)-5-~N-(2-hydroxyethyl)- ';
amino]acetamido-2,4,6-triiodoisophthalamide A solution of 9.50 g ~10 mmol) of the compound ~rom Example '''-33a) and 4.ag g (80 mmol) 2-aminoethanol in 20 ml of ethanol ; are heated overnight at 50 C. The mixture is cooled to room temperature, filtered and dried'in vacuo, with P2O5, to -obtain 7.7 g (95%) of a colourless solid with a m.p. = 216 30 ~ 220-C.
.:
c) N,N'-bi-~-(2,3-dihydroxypropyl)-5-(3-~N-(2,3-dihydroxypropyl) carbamoyl~-5-methoxyacetamido-2,4,6-triiodobenzoyl-N- '' (2-hydroxyethyl3aminoacetylamino)-2,4,6-triiodoisophthalamide To a solution of 30 g (17.2 mmol) of the compound from -~
Example 33b~ in 180 ml of DMA are added 10.01 g (17.2 mmol) --of the compound from Example la) and 21.3 g (74.4 mmol) of ' Na2C03.10H2O- The mixture is stirred vigorouSlY at 21003~8 room temperature overnight. It is filtered and the solvent is evaporated under reduced pressure until dryness. The residue is dissolved in lS0 ml of MeOH which is added to 90o ml of isopropyl alcohol. It is filtered off and dried in vacuo with P2O5. 50 g of a lightly coloured solid are obtained which is purified by breaking it up in 500 ml of isopropyl alcohol and refluxing for 1 hour. It is filtered and washed with ethyl ether (2 x 50 ml), and then dried in vacuo with P2O5 to obtain 41 g of a colourless solid.
These 41 g are dissolved in 200 ml of 50% aqueous methanol.
It is hydrolysed at 40 C with 20~ NaOH, cooled to room temperature and neutralised with 20~ HCl. The solvent is removed under reduced pressure (weight of residue 39 g). 60 -ml to 500 ml of isopropyl alcohol. After filtering and drying in vacuo with P2O5, 36 g (65%) of a colourLess solid are obtained.
d) N,N'bis(2,3-dihydroxypropyl)-5-~3-[N-(2,3-dihydroxypropyl) carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl)amino-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetyl-N-(2-hydroxy-ethyl)amino)-2,4,6-triiodoisophthalamide To a solution of 26 g (17.4 mmol) of the compound from Example 33c) in 65 ml of methanol, are added 34.8 g (91.52 mmol) of Na3P04.12H20. It is stirred for a short while and 7.35 g (91.29 mmol) o~ 2-chloroethanol are added and heated to 60-C. Stirring is continued at 60'C overnight. It is filtered and the alcoholic solvent is removed by evaporation under a reduced pressure. The residue (26.8 g) is purified by preparative liquid chromatography, to obtain ll g (40%) of a colourless solid.
, ' N N'-bis-t2.3-~ihydroxypropyll-5-~3-[N-t2.3-dihvdroxv rooyl) carbamoyll-5-hydroxyacetyl-N-~2-hydroxvethyllamino-2.4 6-triiodobenzo~aminoacetyl-N-(2-hydroxyethyl~amino~-2.4 6-triiQdoisophthalamide (lCJ - 791) :.. . . :.: ; - ; , . ~ ............ . . .
- . - , . . .
3 ~ ~
To a solution of 16 g (11.16 mmol) of the compound from Example 18, in 40 ml of methanol are added 22.3 g (58.70 mmol) of Na2P04.12H20. It is stirred for a short while and heated to 60~C, and 4.67 g (58.00 mmol) of 2-chloroethanol are added. Stirring is continued at 60 c overnight. It is then filtered and the alcoholic solvent is removed from the solution and washings by evaporation at reduced pressure. The -residue is purified by preparative liquid chromatography to obtain 8 g (47%) of a colourless solid.
N N'-bis-(2 3-hydroxypropyl~-5-l3- r N-(2.3-dihydroxypropyl)-carbamoyl1-5-methoxyacetyl-N-r2-hydroxyethyl)amino-2.4.6-tri-iQdobenzoyl-N-methylaminoacetyl-N-(2-hydroxyethyl~amino~-2~4~6 triiodoisophthalamide -~-(l~J - 1091) , a) N,N'-bis-(2,3-dihydroxypropyl)-5-methylaminoacetamido-2,4,6-triiodoisophthalamide 9.50 g (10 mmol) of N,N'-bis-(2,3-dihydroxypropyl)-5-chloro-acetamido-2,4,6-triiodo-isophthalamide, 20 ml of 33% ethanolic ~ -methylamine and 20 ml of ethanol, are heated at 40 C for ~ ;
hours. The reaction product dissolves in a short while, and during the course of the process precipitates abundantly.
It is ~iltered off and dried in vacuo with P205 to obtain 7 g (90%) of a colourless solid. -.. . .
b) N,N'-bis-(2,3-dihydroxypropyl?-5-(3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetamido~-2,4,6-triiodoisophthalamide To a~solution of 28.9 g (17.2 mmol) of the compound from Example 35a) in 180 ml of DMA are added 10.01 g (17.2 mmol) ---of the compound from Example la) and 21.3 g (74.4 mmol 03.10H20. It is stirred at 60 C overnight and the solvent is evaporated under reduced pressure until dryness . `~
The residue is dissolved in 120 ml of MeOH and added to 650 ~~~
.. . .
- ml of isopropyl alcohol. It is filtered and dried in vacuo .:
21003~8 with P2O5. 51.2 g of a slightly coloured solid are obtained. This solid is dissolved in 250 ml of 50% aqueous methanol and hydrolysed with 20% NaOH at 40 C. It is cooled to room temperature and neutralised with 20% HCl. The solvent is removed under reduced pressure (weight of residue 49 g), 150 ml of methanol are added and the methanolic solution is added to 650 ml of isopropyl alcohol. Once the addition has been ended, it is filtered. It is dried in vacuo con P2O5, to obtain 39 g (72%) of a colourless solid.
c) N,N'-bis-(2,3-dihydroxipropyl)-5-(3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl)amino-2,4,6-triiodobenzoyl-IN-methylaminoacetyl-N-(2-hydroxy-ethyl-amino)-2,4,6-triiodoisophthalamide To a solution of 31 g (21.2 mmol) of the compound from Example 35b) in 80 ml of methanol is added 42.4 g (111.51 ), 3 4 1 2 It is heated to reflux and 7.2 g (89.04 mmol) of 2-chloroethanol are added. Heating is continued with reflux overnight. It is filtered and the solvent removed under reduced pressure. The residue ~16.6 g) is purified by preparative liquid chromatography, to obtain 18 g ~55%) of a colourless solid.
EXAMpLE 36 N.N-bis-L2 3-dihydroxypropyl)-5-(3-~N-(2,3-dihydroxypropyl~
carbamQy~ _acetamido-2.4,6-triiodobenzoyl-N-(2 3-dihidroxy-propyLLaminoacetamido~-2~4.6- triiodoisophthalamide(lCJ-13sl) a) N-(2,3-diacetoxypropyl)-5-acetamido-2,4,6-triiodo-isophthalamic acid A mixture of 316 g (0.50 ml) N-(2,3-dihydroxypropropyl)-5-amino-2,4,6-triiodoisophthalamic acid, 3.2 ml concentrated sulphuric acid and 390 ml (421 g 4.12 mol) of acetic anhydride are refluxed in 1,200 ml of ethyl acetate. When the reaction has ended, the solid that is formed is filtered off, washed with ethyl ether and dried in vacuo to constant weight.
Yield: 93 % 210 0 3 ~ ~ :
M.p.: 263-264-C (d) . -: . -b) N-t2,3-diacetoxypropyl)-5-acetamidO-2,4,6-triiodo-isophthalamoyl chloride To a solution of 350 g (0.462 mol) of the compound described in Example 36a~ in 1,250 ml of DMA cooled to 5-10 c are slowly added 134 ml (219.6 g 1.85 ml) of thionyl chloride.
When the addition has ended, stirring is maintained at approximately 10 C for 1 hour, it is diluted with 3,000 ml of ethyl acetate and it is poured into 3,000 ml of water. The organic phase is separated and it the aqueous phase is -extracted with 2,000 ml of ethyl acetate. The combined organic phases are washed twice with 1,000 ml of a saturated ;
solution of sodium bicarbonate and once with 1,000 ml of a ~: ~
10% solution of sodium chloride. The extract is dried over ~ ~-anhydrous sodium sulphate, it is then filtered and treated for 2 hours with 30 g active carbon. It is~filtered and evaporated to dryness under reduced presion and the resulting residue is broken up by stirring with 2,000 ml of petroleum ether for 3 hours. It is filtered and dried in vacuo to constant weight.
: . ' , Yield: 90%
m.p.: 203-208-C (AcOEt) ~d) c) N,N-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl) carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-(2,3-di-hydroxypropyl)aminoacetamido)-2,4,6-triiodoisophthalamide It is obtained and purified following the same general procedure described for the compound from Example lb), starting from: 30 g (0.036 mol) of the compound described in Example 13b ) y 27.8 g (0.036 mol) of the N-(2,3- -~
diacetoxypropyl)-5-acetamido-2,4,6-triiodoisophthalamoyl chloride described in Example 36b).
Yleld: 45%
m.p.: 255-268~C~(d) -N.N'-~is-(2,3-dihydroxypropyl)-5-(3-~ 2,3-dihydroxvpropy~
carbamovL1-5-ac~tam~do-2.4.6-triiodobe~zoyl-N-methylacetyl-N-methvlamino~-2 4.6-triiodoisophthalamide (lCJ - 1491) 44.0 ~ (0.0S6 moles) of the compound from Example 36b ) and 47.~ g (0.056 moles) of the compound from Example described in llb) are dissolved in 264 ml of DMA. 32.04 g (0.11 moles) of Na2CO3.10H2O are added, and it is stirre~ at room tempe_ature for 20 hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated from isopropanol.
The product obtained (z 65.5 g) is dissolved in (1:1) met~anol/water and hydrolysed with 5% NaOH at 45-50 C. It is neut-alised and evaporated to dryness: The crude product obtained is purified by preparative liquid chromatography. 20 g of product are obtained.
Yield: 32.7% -20 m.pDecomposes and sinters from 160 C.
.
: - .
N.N'-~iS-Ll-hydroxymethyl-2.3-dihvdroxy~roovl)- 5-~3-rN-(2.3-hvdroxv~ro~vl)carbamovll-5-acetamido-2,4.6-triiodobenzovl-N-me~hylacetyl-N- methylamino)-2.4.6-triiodoi~ophthalamid~ v (lCJ - 1591) 50 g (5.5 x 10 2 moles) of the compound from Example 8a) and 42.83 g (5.5 x 10 2 moles) of the compound from Example 36b) are dissolved in 300 ml of DMA. 31.6 g (O.11 moles3 of - Na2CO3.10H2O are added and the mixture is stirred at room temperature for 20 hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated from isopropanol. The product obtained (~ 69.2 q) is dissolved in (1:1) methanol/water and is hydrolysed with 5% NaOH at 45 -50-C.
It is neutralised and evaporated to dryness and the crude product obtained is purified by preparative liquid chromatography. 25.5 g Of product are obtained.
Yield: 30.8 ~ . m.p.: Sinters and decomposes above 170 C.
,Example 39 210 0 3 3 8 ~
N.N'-bis-(2,3-dihydroxypro~vl)-5-l3-~N-r2.3-dihvdroxv~ropyl) carbamoyl~-s-methoxyacetamido-2.4.6-triiodobenzoyl--N-(2-hvdroxy-3-methoxy~ropyl~aminoacetyl-N-methvlamino~''' ~2.4~6-triiodoiso~hthalamide. ~lCJ-l991) a) N,N'-bis-(2,3-dihydroxypropyl)-S-tN-(2-hydroxy-3-methoxy-propyl)aminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide ' ~ ' SO g (0.062 moles) of the compound from example lla) and 34.3 g (0.12 moles) of sodium carbonate decahidrate are suspended , in 350 ml of DMF. 22.3 g (0.24 moles) of 3-amino-1- , methoxy-2-propanol are added and the mixture is heated to ',- "
lS re~lux ~or 8 hours. It is then filtered and concentrated to dryness. The residue is dissolved in m~thanol an~ ' precipitated with isopropanol. 38 g (Yield: 71.~%) are obtained.
b) N,N'-bis-(2,3-dihydroxypropyl)-3-(3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-trliodo-' -benzoyl-N-(2-hydroxy-3-methoxypropyl)aminoace~yl-N-methyl- ~ ', amino~-2,4,6-triiodoisophthalamide. '~
30 g (0.035 moles) of 39a) and 28.39 g (0.035 moles~ o~ the ~ :-co~pound ~rom example la) are dissolved in 180 ml of DMA.
28.6 g (0.1 moles) of Na2C03.10H20 are added and stirred at ^l'"'"' ' room temperature for 20 h. It is ~iltered and the solution '~', is evaporated to dryness. The residue is dissolved in methanol and precipitated with isopropanol. The crude product ,' obtained is dissolved in (1:1) methanol/water and hydrolysed ' with 5% NaOH at 45 -50-C. It is then neutralised and -~ evaporated to dryness. The crude product obtained is purified by preparative liquid chromatography. 21 g (Yield:
; 38.7%) are obtained. ' Example 40 , , , ; N.N'-bis-(2.3-dihvdroxv~roDvl)-5-/3-rN-(2.3-dihydroxv~ro~yl~
arbamoyl)-5-~yd,~oxyacetvl-N-(,~m,çthoxy~thyl)amino-40 ~ 2.4.6-triiodobenzovlaminoacetyl-N-(2-methoxyethyl~amino)-2.4.~triioisophthalamide. (lCJ-2191) '.. . .
. _ . _ . . . . ... . . .
- 55 - ~
2~ ~338 This is prepared by following the general procedure described for the compound from Example 16) and starting from: 25 g (0.017 mol) of the compound from Example 18, 35.1 g (0.092 mol) of trisodium phosphate dodecahydrate and 6.9 g (0.0?3 mol) of 2-chloro-1-methoxyethane to obtain 20 g of the dimer sought, which is purified by preparative liquid chromatography.
Example 41 .' ' N,N'-~is-t2.3-dihydroxypropyl~-5-(3-rN-r2-hy~roxvethyl!--t~3-dihydroxv~ro~vl)carbamovll-5-methoxyacetamido-2.4,6-triiodobenzoyl-N-methylaminoacetyl-N-methvlamino~--2.4.6-triiodoisoDhthalamide. (lCJ-2291) a) N-(2-hydroxyethyl)-N-(2,3-dihydroxypropyl)-5-methoxy-acetamido-2,4,6-triiodoisophthalamoyl chloride To a cold solution of 23,37 g (35 mmol~ of 5-methoxy-acetamido-2,4,6-triiodoisophthaloyl chloride in 100 ml of DMF
are slowly added a solution of 4.55 g (45 mmol) of triethylamine and 6.08 g (45 mmol) of 2-hydroxyethyl-2,3-dihydroxypropylamin in 30 ml of DMF. Once the addition has been completed, it is heated to 10-15 C. It is s.irred for 2-3 hours and the reaction medium is distributed between 300 ml of ethyl acetate and 400 ml of water. The organic phase is decanted off and the aqueous phase is extracted with ethyl acetate (2x50 ml). The combined organic phases are washed with 5~ sodium bicarbonate ~lx50 ml) and saturated sodium chloride (lx50 ml). It is dried with anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The slightly coloured solid residue is dried in ~acuo with P2O5, to obtain 16.6 g (62%) of product.
b) N,N'-bis-(2,3-dihydroxypropyl)-5-(3-~N-(2-hydroxyethyl) N-(2,3-dihydroxypropyl)carbamoyl~-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~-2,4,6-triiodoisophthalamide. -' ' "
Following the general procedure described in example lb) ~ -. .
21~338 :
and starting with the compound described in 41a) (25 g, 32.6 mmol) and that described in llb) (25.7 g, 32.6 mmol), 33 g (66%) of a crude product is obtained, which is purified by preparative liquid chromatography. ~ -Example 42 N.N'-bis-(2-hydroxyethyl~-N,N'-bis-(2,3-dihydroxypropyl)-S-~3-[N-(2,3-dihydroxypropyl)carbamoyl)-5-acetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~- -2,4,6-triiodoisophthalamide. (lCJ-2391 a) N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxypropyl)- , 5-chloroacetyl-N-methylamino-2,4,6-triiodoisophthalamide 103 g (0.15 moles) of the compound from example 3a) are - -suspended in 30g ml of DMF. 85.8 g (0.3 moles) Na2C03.10H20 , are added and cooled to between 0 and 5 C. A solution of 40.5 g (0.3 moles) of 2-hydroxyethyl-2,3-dihydroxypropylamine in 90 ml of DMF are added, and the mixture is stirred at room temperature for 20 h. The solution is filtered and evaporated to dryness. The residue is dissolved in methanol and precipitated in ethyl ether. 96 g (72.4%) are obtained. ~-. .
b) N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxypropyl)-5-methylaminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide ~ . .
60 g (0.068 moles) of the compound from example 42a) are dissolved in 420 ml of 33% methylamine in ethanol and stirred at room temperature for 2-3 days. The solution is evaporated to dryness and the residue is dissolved in methanol and precipitated from isopropanol. 42 g ,(Yield: 70.3%) are obtained.
.
c) N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxypropyl-5-~3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-acetamido-~; 2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~-2,4,6-triiodoisophthalamide.
.
~ 40 35 g (0.04 moles) of the compound from example 42b) and ~ -.
31 g (0.04 moles) of the compound from example 36b) are dissolved in 210 ml of DMA. 34.3 g (0.12 moles) of Na2C03.10H2o are added and stirred at room temperature for hours. The mixture is filtered and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated with isopropanol. The crude product obtained is dissolved in (l:1) methanol/water and hydrolysed with 5% NaOH at 45-50~C. It is then neutralised and evaporated to dryness. The crude product obtained is purified by preparative liquid chromatography.
23 g (Yield: 37.5%) are obtained.
. .
.
:~, ::
. ~ .-
g (0.064 moles) of 5-phthaloylaminoacetamido-2,4,6-triiodoisophthaloyl chloride are dissolved in 200 ml of DMF.
40g (0.14 moles) of Na2C03.10H20 are added and cooled to between O and S C. 22.6 g (0.14 moles) of 5-amino-2,2-dimethyl-5-hydroxy-1,2-dioxepane dissolved in 50 ml of DMF
are then added and stirred at temperature room during 20 hours. Then, 12.44 ml (12.81 g, 0.28 moles) of hydrazine monohydrate are added and heated to 50-60 C for 8 hours.
The suspended solid is filtered off and the solution is evaporated to dryness. The residue is dissolved in 2N HCl and heated to 50 C for 10 minutes. The suspended solid is filtered off and the solution evaporated to dryness. The residue is precipitated from methanol/isopropanol. 41.2 g (78%) with a m.p. of 170-185 C is obtained.
b~ N N'-~is-fl-hydrQxvmet~yl-2,3-dihydroxy~o~vl~-5-(3-r N-(1-hy~o~ymLe~hvL-2,3-dihydro~y~ropvl~carbamovll-5-methoxi-acetami~Q=~,4,6-triiodobenzoylaminoacetamido~-2.~,6-triiodo-iso~hthalamide.
- ' . :
30.0 g (3.7g x 10-2moles) of the compound from example 5a) and 26 g (3.16 x 10-2moles) of the compound from example 7a) are di~solved in 168 ml of DMA. 27.1 g (9.48 x 10 2moles) of Na2C03.10H20 are added and stirred at temperature room for 20 hours. It is filtered and the solution evaporated to dryness. The residue is dissolved in methanol and precipitated with isopropanol. The crude product obtained is dissolved in methanol/water (1:1) and hydrolysed with 5% NaOH
at 45-50 C. It is neutralised and evaporated to dryness. The crude product ob~ained is precipitated from methanol/iso-propanol. 39g (yield:70%) was obtained with m.p. of 205-260 C
Exa~le ~ 2100338 N.N'-his-~l-hydroxymethvl-2.3-dihydroXypro~yl)-5-~3- ~-(2.3-dihydroxypropyl~carbamoyl~-5-hydroxyacetami~o -2,4.6-triiodobenzQ~ -methylaminoacetyl-N-methylaminol-2~4~6-tri iodo ~ . ~lCJ-390~
a) N N'-bis-(7-hydroxy-4,4-dimethyl- 3,5-dioxep~nyl)-5- : , methyl-aminoacetyl-N-methylamino-2.4,6-triiodolsooht~alamide.
~: , 180 g of the compound from example 3b) (192.37 mmol) are suspended in 1.450 ml of 30% methyl amine in ethanol are ;
warmed to 40'C for 30 hours, during which the transformation is completed. ~ -Methylamine is removed and it is then evaporated to dryness.
Obtained: 171 g (molar yield: 95%).
b~ N N'-bis-(1-hydroxymethvl-2 3-dihydroxvoro~vl)-~-methyl,-aminoacetvl-N-methylamino-2,4.6-triiodoisoohthalamide.
150 g (161.24 mmol) of the compound from example 8a) are dissolved in 500 ml de methanol. 35~ hydrochloric acid is added until a pH=l is reached. It is heated at 40 C until total hydrolysis has taken place. It is then neutralised with 50~ sodium hydroxide and the sodium chloride that is , formed is filtered o~. It is then evaporated to dryness.
Product obtained: 136.5 g (quantitative). -, Thin-layer cromatography under the same conditions as in example 3a) retains the product at the origen.
c) N.N'-bis-(l-hvd~oxymethyl-2.3-dihydroxypropvl)-S-(3-~N-~2.3-dihydroxyp~o~Ll~arbamoyl~-5-hydroxyacetamido -2,4.6-triiQ~s~gn~y~ methylaminoacetyl-N-methylamino)-2~4~6-tr -iodois~thala~ide.
18.7 g (22.0 mmol) of the compound from example 8b) aresuspended in 115ml of dimethylformamide, and 12.6 g of sodium carbonate decahydrate is added followed by 19.8 g (23.72 mmol) of the compound from example 2a). It is ~tirred at room temperature until the reaction is complete. (24 hours).
' ,' , ' `' ., ,., ,' ' ` ' ;
~ - 29 -210~338 The salts are filtered off and it is evaporated to dryness.
Then, the product is dissolved in lO0 ml of methanol and the salts again filtered off. It is precipitated with 600 ml of isopropanol. Crude product obtained: 33.7 g (Yield: 90%).
The acetate groups are hydrolysed and the product purified by ~ -perparative liquid chromatography.
Pure product obtained: 15 g (molar yield 45%).
Exam~le 9 . -:' .
N,N'-b~ -hyd~oxymethyl-2.3-dihvdroxvpro~yl~-5-(3-~N-(2.3-dihvdroxypropyl~carbamovl1-5-methoxvacetamido -2,~,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino)-2.4.6-tri-iodoiso~hthalamide. tlCJ-490~ ~
.-,,. .,:
18.l g (21.2g mmol) of the comDound from ëxample 8b) are - -dissolved in 80 ml of DMF, and 13.2 g (46.13 mmol) of sodium carbonate decahydrate are added. It is stirred for 5 min.
and 18,5 g (22.94 mmol) of the compound from example la) are added. It is stirred at room temperature until the reaction is complete. (24 hours).
The inorganic salts are filtered off and it is evaporated to dryness. The, it is then dissolved in lO0 ml of methanol, -filtered and precipitated with 600 ml of isopropanol. The product is then filtared off and dried.
Crude product obtained: 32 g (Yield 93~).
The acetate groups are hydrolysed and the product purified by preparative liquid chromatography.
Pure product obtained: 15 g (molar yield 46%) ,N'-bis~ hvdroxvmethyl-2,3-dihydroxy~ro~yl~-5- ~^~N- ~
35~ Ll~hydroxymethyl-~.3~di~v~c~v~rrovl~ bamoyl1-5-methoxy- -acetamido -2 4~6-triiodobenzoyl-N-methylaminoacetyl-N-~ethyl-aminot-2.4,6-~ o~oisophthalamide. ~ -690l 2}.9 g (25.76 mmol~ of the compound described in example 8b) are susPended ln lO0 ml of DMF, and 15.9 g (55.57 mmol) of sodium carbonate decahydrate are added. It is stirred for 5 minutes and 22 g (27.76 mmol) of the compound described in example Sa are added. Then, it is stirred at room temperature until the reaction is complete (30 hours). The -;
inorganic salts are filtered off and it is evaporated to dryness. The product is dissolved in 100 ml of methanol (salts are filtered off) and it is then precipitated with 600 ml of isopropanol. It is filtered off and dried.
Crude product obtained: 37 g (Yield: 90%) The acetonide compound is hydrolysed and purified by preparative liquid chromatography.
Pure product obtained: 18 g (molar yield: 45%) Exa~
N,N'~ is-(2.3-dihydroxyproovl~-5-13-rN-(2.3-dihvdroxv-~roovl)carbamovl~-S-hvdroxvacetamido-2.4.~-triiodo- -benzovl-N-methylaminoacetvl-N-methvL~mino~-2.4.6-triiodo-iso~hthalamide. (ICJ-1090~ -a) N N'-bis-f2.3-dihid~oxvpropvl~-chloroacetyl-N-methvl-amino-2,4.6-triiodoisoph~h~lamide.
120 g (0.17 moles) of the compound from example 3a) are suspended in 360 ml DMF. 99.3 g (0.34 moles) of Na2C03.10H20 are added and the mixture cooled to between 0 and S'C. A
solution of 30.7 g (0.34 moles ) of 3-amino-1,2-propanodiol in 90 ml of DMF is added and stirring is carried out for 20 hours . The solution is filtered and e~aporated to dryness. ;~
The residue is dissolved in methanoI and precipitated with ethyl ether.
12,5 g are obtained. (Yield: 94.3%). m.p.: 177-208 C.
b~ N.~'-bis-r~,3-d~ydroxy~opyll-5-methylaminoacetvl-N-methyl~in~o-2 4,6-triiodoisophthalami~e g (0,062 moles) of the compound in example lla) are dissolved in 350 ml of methylamine/ethanol at 33% and the solution stirred at room temperature for 3 days. The solution is evaporated to dryness and the residue : , ~ ,, . _ ,` , . .,: : , ,., , :. : . . :., ., . .. . . . , , .. . :
2 1 ~ ~-3 3 8 dissolved in methanol and precipitated with isopropyl alcohol.
Amount obtained: 33.3 g (Yield : 68%) m.p.: 178-205 C . , .
S c~ N.N'-~is-( 2.3-dihydroxypropyl)-5-~3- r N-t2.3-dihydroxy-~ro~yl)carbamoyl~-5-hydroxyacetamido-2.4.,6-triiodobenzoyl-N-methvlaminoacetyl]-N-methylamino~-2.4.6-triiodoiso-~hthalamide.
30 g (0.038 moles) of the compound from example llb) and 34.87 g (0.041 moles) of the compound from example 2a) ara dissolved in 190 ml of DMA. 32.61 g (0.11 moles) of Na2C03.10H20 are added and the mixture is stirred at room temperature for 20 hours. It is filtered, and the solution is evaporated to dryness . The residue is dissolved in methanol and precipitated with isopropanol. The crude product obtained is dissolved in methanol/water (1:1) and hydrolysed with 5% NaOH at 45-50 C. Then it is neutralised and evaporated to dryness. The crude product obtained (z 35 g) is purified by preparative liquid chromatography. Amount obtained: 20 g (Yield : 36.0%) m.p. : 256-268 C .
E~ElSLL2 N.N'-~L~-~2.3-dihydr~oxy~ropy~-5-~3-rNJ2.3-dihyd~Qx~-~ro~vl~ca~moyl]-5-met~oxyacetamid~,-2.4.6-triiodobenzovl -N-methvlami~oa~etyl_-N-methylamino)-2.4.6-triiodoisophthalamide.
(lCJ 1190) 22 g (0.027 moles) of the compound from example llb) and 24.71 g (0.030 moles) of the compound from example la) are dissolved in 140 ml of DMA. 23.74 q (0.083 moles) of Na2C03.10H20 are added and stirred at room temperature for 20 hours. After filterinq, the solution is evaporated to dryness. The residue is precipitated from methanol/
isopropanol. The product obtained (z 31.4 g) is dissolved in ~ethanol/water (1:1) and hydrolysed with 5% NaOH at 45-50 C.
,~ It is neutralised and evaporated to dryness. The crude product obtained (27.6 g) is purified by preparative liquid chromatography. Amount obtained: 14 g (Yield : 35.1 % ).
m.p.: 257-267~C .
2100338 :Example ~3 N N'-bis-f2.3-dihydroxyDropyl)-5-~3-~N-(2.3-dihVdroxyprOpyl~
carbamovll-5-hvdroxyacetamido-2.4 6-triiodobenzoyl-N-r2 3-S dihydroxypropyl~aminoacetamido)-2 4~6-triiodoisophthalamide.
(lCJ - 191) a) 5-chloroacetylamino-2 4.6-triiodoisophthaloyl chloride To a solution of 100 g (0.16~ mol) 5-amino-2,4,6-triiodo-isophthaloyl chloride in 300ml of DMA and cooled to 0-5 C, are slowly added 39.9 ml (0.502 mol) of chloroacetyl chloride. It is allowed to return to room temperature and is stirred for 6 hours. The reaction product is diluted with ~
700 ml of ethyl acetate and it is poured over lOOOml of water, -the organic phase is separated anc extracted with 2x150 ml of ethyl acetate. The combined organic phases are washed with 2x150 ml of saturated sodium bicarbonate solution and with 250 ml of 10~ sodium chloride solution. It is dried over anhydrous sodium sulphate, filtered and concentrated in vacuo until an abundant precipitate appears. After filtering it is washed with ethyl ether and dried ln vacuo. 95 g (84%) of the desired product are obtained.
Thin-film chromatography ttoluene) : R~ - 0.20 m.p.: 250-260-C (ethyl acetate) b) N.~ is-~2.3-dihydroxyproovl~-3-rN-(2.3-dihydroxvproDvl) amino~çetamidol-2.4.6-triiodoisophthalamide.
A mixture of 80 g (0.120 mol) of the product described in example 13aj, 119.2 g (0.416 mol) of sodium carbonate decahydrate and 76 g (0.834 mol)of 3-amino-1,2-propanodiol in 320 ml of DMF are heated to 50-60 C for 8 hours. It is filtered and concentrated in vacuo to dryness. The residue is dissolved in 240 ml of methanol, the salts that are precipitated are filtered off, and the product is precipitated in 2000 ml of isopropanol. It is filtered off and washed with ethyl ether.
-~338 The solid obtained is redissolVed in 400 ml of methanol and precipitated in 2000 ml of ethanol. After filtering, it is washed with ethyl ether and dried in vac~lo. In this way, 80 g (80~) of the desired product are obtained.
m.p. = 140-153-C
.. .
c) N N'-bis-~2.3-dihydroxypropyl~-5-(3- r N-(2.3-dihydroxy-proovl)carbamoyll-5-hydroxyacetamido-2.4.6-triiodobenzovl--N-(2.3-dihvdroxyproovl~aminoacetamido~-2.4.6-triiodo-iso~hthalamide. -"
Following the general procedure described example lb) and starting ~rom the compound described in example 13b) (30 g, 0.036 mol) and that described in example 2a) (29.9 g, 0.036 mol).
Yield crude product: 75%.
. , .
Examole 14 .
N.N'-bis-(2-hydroxyethvl)-5-/3- CN ~ 2.3-dihvdroxvoro~vl)-carbamoyll-5-hydroxyacetamido-2.4.6-triiodobenzoyl-N-(2, 3-dihydroxvetil~aminoacetamido~-2 4,6-triiodoisoohthalamide.
(lCJ-103) 2S Following the general procedure described in example lb) and starting fro~ N,N'-bis(2-hydroXyethyl)-5-[N-(2-hydroXyethyl)-aminoacetamido~-2,4-6-triiodoisophthalamide (described in DOS
292~417 ) (30 g, 0.040 mol) and the acid chloride described in example 2 aj.
~Yield of crudæ product:77%.
Example 15 : N ~ N ~ -~i s - ( 2 ~ 3~-dihyd~oxypropyl ~ -5- ~ 3 - r N- ( 2 ~ 3 -dihydroxv~ro~yl ) 35~ ~ carbamoyll~5-methoxyacetamido-2.4.6-~riiodobenzoyl-~ N-(2.3-dihydroxy~r~ inoacetamidol-2.4.6-triiodo-r ~ Q_b9~ ~ (lCJ-391) Followlng the general procedure described in example lb) and -starting from the compound described in example 13b) (30g, a :~
., . . . ' ... . . . .
~ 34 0.036 mol) and the acid c~ ~ scribed in example la) (28.9 g, 0.036 mol).
Example 16 S ' . :
N.N'-bis-r2-hvdroxyethyll-5-~3- r N-~2,3-dihydroxyoropvl)-carbamovll-5-hydroxyacetyl-N-(2-hvdroxvethyl)amino-2,4.6-tri-iodobenzovL-N-r2-hydroxyethvl)amino-acetvl-N-(2-hvdroxyethyll-amino)-2~6-triiodoisoohthalamide~ (lCJ-291) A mixture of the compound describe~ in example 14 (ICJ-103) (23 g, 0.016 mol), trisodium phosphate dodecahydrate (32.4 g, 0.085 mol) and 2-chloroethanol (4.6 ml, 5.48 g, 0.068 mol) in methanol (60 ml), are refluxed for 2 to 3 days.
The crude product of the reaction is filtered, evaporated to dryness at reduced pressure, and the residue is purified by ~-preparative liquid chromatography.
Yield: 5~S m.p.: 215-238-C (decomposes) .-ExampLe 17 :.
N~N~-bis-(2-hydroxyethyll-5-~3-rN-!2~3-dihydroxvoroovl)-.. . .
carbamovll-~-methoxvacetamido-2.4,6-triodobenzovl-N-(2-25 hvdroxyethvllaminoacetamido~-2.4.6-triiodoiso~hthalamide.
(lCJ-105) Following the general procedure described in example lb) and starting from N,N'-bis(2-hydroxyethyl)-5-~N-(2-hydroxyethyl)-aminoacetamido)-2,4,6-triiodoisophthalamide described in DOS
2928417 (30 g, 0.040 mol) and the acid chloride described in -~1 example la) (32.4 g, 0.040 mol).
. Yield of crude product: 80%. -~
Example 18 N~N~-bis-(2~3-dihyd~oxypropyl)-5-~3-rN-(2~3 carbamoyll-5-hydroxyacetamidol-2.4,6-triiodobenzoylamino-acstamido)-2.4.6-triiodoisophthalamide. (lCJ-790) ', .
210~3~8 :
Following the general procedure described in example 1 b) and starting from N,N'-bis(2,3-dihydroxy-propyl)-5-amino-acet-amido-2,4,6-triiodoisophthalamide (20g, 0.026 mol) and the acid chloride described in example 2a) (26.3 g, 0.031 mol).
In this case, the crude is purified by recrystallisation in s water.
Yield: 76% m.p.: 230-270 (decomposes) Example 19 N,~'-bi~-(L-hydroxv~ethyl-2.3-dihvd~QxvprQpvl)-5-l3-[N- -(2,3-di~ydroxYpropvl~carbamoyll-5-hy~oxyacetamido-2,4.6-triiodobenzovlaminoacetamidot-2.4.6-triiodoisoohthalamide.
(lCJ-158g) 1 5 . : . ., 28.0 g (3.3xlO 2moles ) of N-(2,3-diacetoxypropyl)-5-acetoxy-acetamido-2,~,6-triiodoisophthalamoyl chloride, described in example 2a) and 23.0 g (28xlO 2 moles) of the compound described in example ~a) are dissolved in 150 ml of DMA.
20.8 g (7.26xlO moles) of Na2C03.10H20 are added and stirred at room temperature for 20 hours. The salts are filtered off and the solution evaporated to dryness. The residue is -dissolved in methanol and precipitated in isopropanol. The product obtained (34.0 g) is dissolved in water/ methanol (1:1) and hydrolysed with 5% NaOH. It is neutralised and evaporated to dryness. The crude product obtained is~; !:' " ' precipitated in methanol/isopropanol. 27.5 g were obtained (Yield: 65.7~) m.p.: 200-255-C.
Exam~le 20 . ~
N.N'~ hyd~ xymethyl-2.3-dihydroxypropyl~-S-~3-rN-(2.3-dihvdroxypropy~carbamoyl]-5-methoxyacetamido-2.4 6-triiodobenæoylaminoacetamido)-2.4.6-triiodoisolphthalamide.
(lCJ-168s) ---~'~: : . .
23.5 g (0.02g moles) N-(2~3-diacetoxypropyl-2~4~6-triiodo--.:
._~ ... .. .
isophthalamoyl chloride, desc~i~Q~ ~n3~xample la) and 20.0 g (0.043moles) o~ the compound described in e~ample 7a) are dissolved in 110 ml oS DMA . 20.8 g (O.072 moles) of Na2C~ OH20 are addec and s.ir~ed at room temperature for 2~
hours. The salts in suspensicn are filte-ed Off and the solution is evaporated to dryness. The resicue is dissolved in met~anol and precipitated in isopropanol. The produc_ -obtained (40 g) is dissolved i~ methanol/wz.ar (1:1) znd hydrolyseA with 5% NaO~ a- 4 -~0 C. The product is neut-al seA an~ evapcrated t~ c-yness. The c~ude prcduc-obta-'ned is pre~ipita'e~ in meth2~cl/isopropa..cl. 28.7 g cr produc_ is obtained (78.4~). m.~.: 200-280 C.
Exam~le 2.1 N~N~-~ls~ hv~~~xvme',~L;z~ x~r~cv~-^-i 3 - r N- ( 2 .: -dihvd~ vl~carbamov~ -me_:-xy2ce~amidc-:.4.6-t-lioc~
benzov'-~ ethvlamino2c~tamido~ 6-t~~iodc-se-nt~zlam-ce.
(ICJ-1~91) :.
' ' a) N,~'^b~s-(l-hvdrcxvmethvl-2, -d hvdroxv~roc~ methv'-aminoacs~2mido-2,4,6-t--iodoiso~ a21amide.
? 5 Following t~e procedura used in ex2mple 24b) and s~ar~ nc ~rom from 40 g (40.3 mmol) c~ N~N~-bis-(/-hidroxv-al4-dimethyl-3,_-dioxepanyl)-5-chlcr~zc_tamido-2,4,0-triiodo-ls -pht.~a}amide, (example 22a), and ~v means of the cor-esponc na acid hydrolysis at 40 C, a syr-pv residue is obt~ined wh-ch is precipi-~ted by means of me-~anol-isopro~anol. AL~e_ filteri~a and dryina with P20g, ~.3 S (~8%) o~ a slightlv coloured solid is obtained. ' '' b~ -bis-~1-hvdroxv~ethvl-2.3-d hvdroxv~ro~vl~-5-t3-r~ , 2 3-dihvdroxy~roovllçar~amovL ~ ethoxvacetam d~-2.4.6-triicdoben20vl-~-~ethvlamincacstamido)-2 ~.6-t-i-iodoisophth~amide.
-~ suspension of 2S a (29.9 ~mol) of U~N~-~is-(l-hydr methyl-2~3-dihydroxypropyl)-5-methylaminoacet~mido-2~4~6-.
-æ~0~33s triiodoisophthalamide, (previous example) is stirred at room temperature for 10 hours with 24.1 g (29.9 mmol) N-(2,3-diacetoxypropyl)-5-methoxyacetamido-2,4,6-triiodoiso-phthal-amoyl chloride, (example la) and 17,1 g (59.8 mmol) of sodium5 carbonate decahydrate in 200 ml of DMA. It is filtered and the solvent removed under reduced pressure. The residue is dissolved in methanol and precipitated from isopropanol.
The product is filtered and dried in vacuo, to obtain 62 g of a slightly coloured product. This solid is hydrolysed in an a~ueous alcoholic solution with 20~ NaOH. It is neutralised with 20% HCl and the solvent is removed under reduced pressure. The residue is dissolved in methanol and precipitated from i~opropanol. It is filtered and dried in vacuo to obtain 34 g (75%) of a slightly coloured solid which is purified by preparative liquid chromatography.
. .: -. -~ .
Exa~nl~
..
20 N~N~-bis-(l-hydroxvmethvl-2~3-dihvdroxvpro~vl~-5-l3-rN-~2~3~
dihydrqxy~opvllcarbamovl~-5-methoxyacetamido-2 a 6-triiodo-benzovl-N-L~-~yd~o~yethyl)aminoacetamido~-2.4.6-t-iiodo-iso~hthalami~de~ (lCJ-16~1) -25 a~ N,N -bis-(4.4-dimethvl-7-hydroxy- 3.5-dioxepanvl~-5-chloro-acetamido -2.4.6-triiodoiso~thalamide.
A suspension of S-chloroacetamido-2,4,6-triiodoisophthaloyl chloride (134 g, 0.2 mol) described in example 13a), sodium 30 carbonate decahydrate (172 g, 0.6 mol) and 6-amino-2,2-dimethyl-1,3-dioxepane-5-Ql (32g, 0.2 mol) are heated to 55 C - --for 12-24 hours in acetone (400 ml). The solvent is removed in vacuo and the residue crushed with water. It is filtered of~ and dried in vacuo. Yield: 52%.
b~ N.N -bisLl-hydroxymethvl-2.3-dihydroxy~ropyl~-5-rN-2-hydroxyethyl)aminoacetamidol-2.4.6-triiodoiso~hthalamide.
A suspension of the compound (50g, 0.54 mol) as obtained in ;~ -: :
~ :., .
., ~, . ~.. .... . .. . . . . ... . .~ .... .... .. . .. . . . . . .
2100~
the previous section a), and 2-aminoethanol (8.1 ml, 7.98 g, 0.131 mol) is heated in ethanol (200 ml) at 50'C for 3 days.
When the transformation into N,N'-bis-(4,4-dimethyl-7-hydroxy-3~5-dioxepanyl)-s-[N-(2-hydroxyethyl)aminoacetamido]-2,4,6-triiodoisophthalamide - which is not isolated - is complete, the reaction medium is diluted with ethanol (200 ml) and hydrolysed by acidulating with hydrochloric acid.
It is evaporated to dryness at reduced pressure and the residue is dissolved in methanol and precipitated in isopropanol. Filter and dry in V2C'10.
Yield: 73%.
: '.
c) N L~ -bis-(1-hvdroxy~ethvl-2,3-~ihvdroxv~roovl~-5-~3- rN-~ -1~ (2,3-dihydroxypropvl)carbamov' -5-methoxvacetamido-2.~ 6- -triio~obenzovl-N-~2-~vdroxvethvl~aminoacetamido~-2.4 6-triiQ~o-iso~hthala,m~,de,. : ~ "
Following the general procedure described in example lb) and starting ~rom the compound descr ~ed in the previous section b) (23 g, 0.027 mol) and with t:~e acid chloride in example la) t21.41 g, 0.027 mol). -Yield of crude product: 70%.
'' ~
: : ' :
, ~ ~ ; - , ,, -2l0a33s N~Nr-bis-~2~3-dihydroxy~ro~vl~-5-~3-rN-(2-~3-hvdrcxvpro~vl~ :
car~amovll-s-acetamido-2.4 6-triiodobenzovl-N-(2.3-dihydroxv-Pro~vl)aminoacetvl-N-methvlamino~-2.~6-triiodoisophthalamide.
(lCJ - 1891) a) N,N'-bis-(2,3-dihydroxypropvl)-5-i3-~N-(2,3-dihydroxypropvl) -aminoacetyl-N-methvlamino~-2,4,6-triiodoisophthalamide.
1 0 ~ ' This is prepared following the pr~cedure desc-ibed in Example 13b), and starting f~om 5-c~lorvacety7-N-methylam1no-2,4,6-triiodo-~sophthaloyl chloride des~~ibed in Example 3 (82.3 g, 0.12~ mol), sodium carbonate decahvdrata (120.1 ~, 0.420 mol) and 3-amino-1,2-propanodiol (54.6 c, 0.600 mol).
Yie7d: 78%.
b) N,N'-_is-(2,3-dihydroxypropyl)-_-~3-~N-(2,3-dihydr~xy-prooyl)carbamoyl]-5-acetamido-,~,4,6-t~iiodcoenzoyl-N-(2,3-dihydroxypropyl)aminoacetyl-N-~e~hylamino-2,4,6-t-iiodo- -~
isophthalamide.
Followina the general procedure des~ribed in Example lb) and star~ing rom the compound descr,_ed in the pravious section -~
a) (40 g, 0.047 mol) and t~e ch ~ride of t;~e acid described in Example 36~) (36.53 g, 0.047 moi).
Yield: 76%.
E~AMPLE 44 . ~
N N'-~is-~,3-dihvdroxv~ro~vl)-N.N'-dimethvl~ 3-rN-(2,3-dihvd~oxv~r~vl~car~amovll-~-nvdr~xvacet~mido-' ~,6-t-llodo- 7 benzov~-N-~ethylaminoa~tvl-N-methvlamino~-triiodo-iso~thalamide. (lCJ - 890) a) N,N'-~is-(2,3-dihydroxypropyl)-~,N'-dimethyl-5-chloroacetyl-methylamino-2,4,6-~~iiodoisophthalamide.
118 g (0.77 moles) 5-chloroacetyl-N-methylamino-2,4,6-triiodoisophthaloyl chloride are suspended in 240 ml of DMF.
97.28 g t-74 moles) of Na2C03.10H20 are added and the solution cooled to between 0 and 5 C.
. ~ .
.: .
- 4o2l~o3~8 Once this temperature has been reached, 39.7 g (0.34 moles) of N-methyl-3-aminopropano-diol is added dropwise, dissolved in 65 ml of DMF. Once the addition has been ended, it is allowed to return to room temperature and it is stirred for hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The resulting residue is dissolved in 200 ml of methanol and precipitated by addition into one litre of ethyl ether. The solid that is precipitated is filtered off, washed with ether and dried in vacuo. 131.2 g are obtained.
(Yield: 93.7~). m.p.: 130-165C.
b) N,N'-bis-(2,3-dihydroxypropyl) N,N'-dimethyl-5-methyl-aminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide A solution of 70g (25 mmol) of N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-chloroacetyl-N-mezilamino-2,4,5-triiodo-isophthal~amide and 70 ml of 33% alcoholic methylamine in 140 ml of ethanol is heated at 40 C fo 30 hours. It is cooled to room temperature and filtered. The solvent is removed under reduced pressure. The residue is dissolved in 100 ml of methanol and this is added to 200 ml isopropyl alcohol. once the addition has been finished, it is stirred for a few minutes and filtered. The solid is washed with isopropyl alcohol and ethyl ether, and then dried in vacuo over P2O5. 41.9 g (52%) of a colourles ~olid is obtained.
c) N,N'-bis-(2,3-dihydroxylpropyl)-N,N'-dimethyl-5-~3-[N-2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylamino acetyl-N-methylamino)-triiodoisophthalamide To a solution of 2.3g (26 mmol) of N,~'-bis-(2,3-dihydroxy-propyl)-N,N'-dimethyl-5-methylaminoacetyl- methylamino-2,4,6-triiodoisophthalamide in 270 ml of DMA are added 22.3 g (78 ) of Na2CO3.10H2o There is then added 22.7 g, (28.6 m~ol) of the chloride described in Example 2a), the mixture is stirred at room temperature until the following day and it is evaporated to dryness at reduced pressure (weight of the residue: 50.2 g).
The residue is dissolved in 1:1 aqueous methanol and is hydrolysed with 5% NaOH at 40 C. It is cooled to room temperature and neutralised with 20% HCl. The solvent is removed at reduced pressure and 100 ml of methanol is added to the residue. The methanol solution is added to 1000 ml of isopropyl alcohol. Once the addition has been ended, it is stirred for a few minutes and filtered. The product is dried in vacuo over P2O5, and purified by preparative liquid chromatography.
. .
N,N'-pis-(2,3-dihydroxypropyl~-N.N'-dimethyl-5-13-~N-(2~1,3,,-d -hydroxypropyl)carbamoyl~-5-methoxyacetamido-2~4~6-triiodo-benzoyl-N-methylaminoacetyl-N-methylamino)-2 4 6-triiodo- :
iso~hthalamide (lCJ - 990) ;
To a solution of 21.3 g (26 mmol) of the compound from example 24b) in 270 ml of DMA, is added 22.3 g (78 mmol) of Na2CO3.10H2O and 23.06 g (28.6 mmol) of the compound from Example la). It is stirred at room temperature overnight.
It is filtered and evaporated to dryness at reduced pressure.
(weight oE the residue 51.2 g). ~
,:. ''. :
~he residue is dissolved in 50% aqueous methanol and hydrolysed at 40'C with 20% NaOH. It is cooled to room temperature and neutralised with 20~ HCl. The solvent is removed at reduced pres8ure and the residue treated with 100 ml of methanol. The methanolic solution is precipitated with 1000 ml of isopropyl alcohol. After stirring for 5 minutes it is filtered, then dried in vacuo and filtered off, followed by drying in vacuo over P2O5. 30 g of a slightly coloured solid are obtained which is purified by preparative liquid chromatography. 19.9 g (51%) of a colourles solid is obtained.
. ~ . .
EXAM~LE 26 ~ -N.N'-bis-r2.3-dihydroxypropyl~-N.N'-dimethyl-5-~3-rN-~2.3-ihvdroxypropyl)carbamoyll-5-hydroxyacetamido-2.4.~-triiodo-ben~oy~aminoacetyl-N-methylamino~-2,4,6-triiodoiso-phthalamide ~lCJ - 1290) 20 g (0.023 moles) of the compound from Example 2a) and S ' ~ ?, ~
17.51 g (0.021 moles) of N,N'-bis-~2,~-dihydroxypropyl)-N,N'-dimethyl-5-aminoacetyl-N-methylamino-2,4,6-triiodoiso-phthalamide are dissolved in 112 ml of DMA. 18.12 tO. 06amoles) Na2C03.10H20 are added and it is lef~ to stir at ro~m temper~ture for 20 hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated in isopropanol.
The product ootained (x 24 g ls dissolved in methanol/water (1:1) and hydrolysed with 5% NaOH at 45-_0 C. It is neutralised and evaporated to dryness. The crude produc-obtained is purifie~ by preparative liquid chromatographv.13.2 g. is obtained.
(Yield: 41.2 %) m.p.: 110 - 210-C.
EXAMP~ 2, N,N'-bis-(2,3-dihydroxvpropylj-~,N'-dimethvl-~-~3 rN-(2,3-dihydroxypropyl)carbamoyl¦-methoxyacetamido-2,4,6- -triiodobenzoylaminoacetvl-N-methylamino~-2,4,6-triiodo-iso~hthalamide (lCJ - 1390) 19.3 g (0.024 moles) of the c~mpound from example la) and 17.5 g (0.021 moles) of the compound described in DOS 2 928 417 are dissolved in 112 ~1 of DMA. 18.3 a (O.06~ moles) o~
Na2C03.10H20 are added and stir.ed at room temperature for 20 hours. The insoluble sal~s are filtered off and the solution evaporated to dryness. The product obt~ined (z 27 g) is dissol~ed in (1:1) water/methanol and hydrolysed with 5%
NaOH at 45-30 C. It is neut~alised and evaporated to dryness. The crude product is purified by preparative liquid chromatography. 14.5 g. are obtained. (Yield: 44.Q~) m.p. Sinters and decomposes betwe~n 140 y 230 C.
t-bis~ 3-dihvdrox~2ropvl~-5-(~-rN-(2~3-dihvdroxv~r car~amoyll 5-~ethoxyacetamado-2 4 6-t~LL~lS~æL~9&l~in acetyl-N-methvlamino)-2 4~6-triiodoiso~hthalamide.
(lCJ - 1590) ~ . . . . .. . .. ... .. . . . .. ... .
210~33~
a) N~N~-bis-(2t3-dihydroxypropyl)-5-aminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide -50 g (0.062 moles) of 5-phthaloylamino-acetyl-N-methylamino-2,4,6-triiodoisophthaloyl chloride are dissolved in 150 ml of DMF. The mixture is cooled to between 0 y 5-C and 36.48g of :
Na2C03.10H20 (0.124 moles) and 11.4 g (0.124 moles) of 3-amino-1,2-propanodiol dissolved im 50 ml of DMF, are added.
It is left stirring at room temperature for 24 hours. 12 ml (0.25 moles) of hydrazine hydrate are added. The mixture is heated to 50-C for 3 hours. The suspended solid is filtered off and the solution evaporated to dryness. The residue is dissolved in 2N HCl and heated at 50-C for 10 minutes. The suspended solid is filtered off and the solution evaporated to dryness. The residue is precipitated from methanol/
isopropanol. 24.0 g are obtained.
(Yield: 50S). m.p.: 220-230-C.
b) N,N'-bis-(2,3-dihydroxypropyl)-5-(3-tN-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl- - -aminoacetyl-N-methylamino -2,4,6-triiodoisoDhthalamide . .
. ' -21.72 g (0.027 moles) of the compound described in Example -;
la) and 19.0 g (0.024 moles) of N,N'-bis-(2,3-dihydroxy-propyl)-5-aminoacetyl-N-methylamino-2,4,6-triiodoisophthal-amide are dissolved in 122 ml of DMA. 21.03 g (0.073 moles) of Na2C03.10H20 are added, and stirred at room temperature for 20 hours. The insoluble salts are filtered off and the solution evaporated to dryness. The residue is dissolved in methanol and precipitated in isopropyl [alcohol]. The product obtained~ (~ 32 g ) is dissolved in (1:1) methanol/water and hydrolysed with 5% NaOH at 45-50-C. The solution is neutralised and evaporated to dryness. The residue is recrystallised from water. 14.4 g. of product is 3S obtained. (Yield : 40.2 % ). m.p.: Sinters and decomposes between 130-210-C.
N.~ N~N~-tetraki~-(~-hydrox~ethyl~-5-f3- r N-(2~3-dihydroxyprs~LL
- 44 ~ 21 0 ~3~ 8 carbamQvll-5-hydroxyacetamido-2~4~6-triiodobenzoyl-N-methyl~
aminoacetyl-N-methyl~mLnQ~-~.4 6-triiodoiso~hthalami~dç (lCJ-1690) a) 5-chloroacetylmethylamino-N,N,N',N'-tetrakis-(2-hydroxy-ethyl)-2,4,6-triiodoisophthalamide ~ --To a solution of 27.5 g (40 mmol) of the compound in Example ~-3a) in 85 ml of DMF is added 22.9 se anaden 22.9 g (80 mmol) f Na2C3 lH2 It is cooled to 10 C and to it is added a solution of 8.83 g ~84 mmol) of diethanolamine dissolved in 8 -11 ml of DHF. Once the addition is completed, it is warmed to ambient temperature for three hours and the solvent is removed undèr reduced pressure to obtain a solid residue (16 g). The residue is dissolved in MeOH and 500 ml of ethyl ether are added. Once the addition is complete, it is `
stirred for a moment and filtered, and dried in vacuo over ~ -P2O5. 28 g of a slightly coloured solid are obtained which is purified by c.c. flash (acetone/MeOH 2:1). 19.6 g (60%) ~-of a colourless solid are obtained with a m.p. of 60-98 C.
: ' :, b) 5-methylaminoacetyl-N-methylamino-N,N,N',N'-tetrakis-(2--hydroxyethyl)-2,4,6-triiodoisophthalamide , .; .
A suspension of 70 g (85 mmol) of the compound in Example -29a) in 140 ml of ethanol and 70 ml of a 33% methylamine in ethanol solution are stirred together at 40-C for 30 hours.
It is filtered and evaporated to dryness. The residue is dissolved in 120 ml of methanol and it is added to 900 ml of isopropyl alcohol. When the addition has ended , it is filtered and dried in vacuo over P2O5. 21.8 g of a colour- -less solid is obtained which is purified by flash c.c.
(CHCl3~Me0H 3:2). 15.1 g (22%) of a colourless solid is obtained.
c) N,N,N',N'-tetrakis-(2-hydroxyethyl)-5-~3-[N-~2,3-dihidroxy--propyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~-2,4,6-triiodo-isophthalamide To a soIution of 21.~3 g (26 mmol) of the compound of Example 29b) in 270 ml of DMA is added 22.3 (~8 mmol) Na2C03.10H2O
and 22.7 g ~28.6 mmol) of the compound of Example 2a).
_ 4521 003~8 It is stirred at room temperature overnight and filtered at reduced pressure (weight of residue: 52.3 g.). ~
The residue is dissolved in 50% aqueous methanol. It is then -, hydrolysed at 40 c with 20% NaOH, cooled to room temperature and neutralised with 20% HCl. The solvent is removed under -reduced pressure and the residue is treated with 200 ml of methanol. The methanol solution is precipitated in 1000 ml of isopropyl alcohol. It is filtered off and dried in vacuo with P205 to obtain 34.6 g of a yellowish solid which is purified by preparative liquid chromatography. 16.6 t43%) of a colourless solid is obtained.
N.N,N'.N',l'-tetrakis-f2-hydroxyethyl ! - 5-(3-~N-(2.3-dihydroxy- ~-~ropyl~carbamoyll-5-methoxyacetamido-2.4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino -2.4.6-triiodo-isophthalamide (lCJ - 1790) To a solution of 17 g (20.8 mmol) of the compound from Example 29b) in 215 ml of DMA, are added 17.85 g (62.4 mmol) Na2C03.10H20 and 18.5 g (22.9 mmol) of the compound from Example lal, and the whole is stirred at room temperature for a night. It is filtered and evaporated to dryness under reduced pressure (weight of the residue 29 g.) .
The residue is dissolved in 50% aqueous methanol, and hydrolysed at 40 C with 20% NaOH. It is cooled to room temperature and neutralised with 20% HCl. The solvent is removed under reduced pressure. The residue is treated with methanol and the methanol solution is precipitated with isopropyl alcohol. Once the precipitation has finished, it is stirred for a moment, the product is filtered off and dried in vacuo over P205. 23.7 g of a slightly coloured solid is obtained which is purified by preparative liquid chromatography.
15.6 g (50~) of a colourless solid is obtained.
~1~03~8 ~-EXAMPLE 3l N.N.N'.N'-tetrakis(2-hydroxyethyl~-5-~3-~N(2.3-dihydroxv-~ropyl)carbamoyll-5-methoxvacetamido-2.4.6-triiodQbenzoyl-aminoacetamido)-2,4~ 6-triiodoisophthalamide (lC~ - 1890) a) 5-phthalimidoylacetamido-N,N,N',N'-tetra-kis-(2-hydroxy-ethyl)-2,4,6-triiodoisophthalamide - -To a solution of 31.3 g (40 mmol) of S-phthalimidoylacet-amido-2,4,6-triiodoisophthaloyl chloride in 85 ml of DMF is added 22.9 g (80 mmol) of Na2C03.lOH20. It is cooled t~
lO C and 8.83 g (84 mmol) of diethanolamine in 8 ml of DMF
are added. once the addition has been completed, it is warmed to room temperature and stirred overnight. It ls lS filtered and evaporated to dryness at a reduced pressure.
Finally, it is broken up in 50 ml of water. It is filte~e~ -off and dried in vacuo ove~ P205, to obtain 20.2 (55%) o~ a colourless solid.
b) 5-aminoacetamido-N,N,N',N'-tet-akis-(2-hydroxyethyl)-2,4,6-triiodoisophthalamide A suspension of 60 (65.2 mmol) of the compound from Example 31a) in 210 ml of ethanol is refluxed, and 13.05 g (260.8 mmol) of NH2-NH2.H20 are added, the product of the reaction redissolving a~ter a few minutes. After 7 hours, it is cooled to room temperature and the solvent is removed unde_ reduced pressure from the reaction medium. The residue is stirred at 40-C with 250 ml of 5% ~Cl for one hour. It is cooled to room temperature and filtered. The filtrate is evaporated to dryness under reduced pressure. 50 ml of MeO~
are added and it is then left in the refrigerator overnight.
The hydrazine hydrochloride is filtered off and the filtrate is concentrated to 2/3 of its initial volume, and it is again left in the refrigerator overnight. The product is filtered o~f and washed with methanol (l x lO ml) and ethyl ether ~l x lO ml) and dried in vacuo over P205. 18.l g (74%) of a colourless solid is obtained.
c) N,N,N',N'-tetrakis-(2-hydrOxyethyl)-5-~3-[N-(2~3-dihydroxy- --propyl)carbamoyll-5-methoxyacetamido-2,4,6-triiodo-benzoyl- --3 3 ,~
aminoacet~mido~-2,4,6-triiodoisophthalamide.
To a solution of 20 g (25.3 ~mol) of the co~pound from E~ample 31c) in 200 ml of DMA are added 21.7 (75.9 ~mol) Na2C03.lOH20 and 22.5 g (27.8 mmol) of the compound from Example la). It is stirred at room temperature overnight.
It is filtered and the solvent removed under reduced pressure (weight of residue S2 g).
The r~sidue is dissol~ed in 200 ml of 50~ aqueous met~anol and hydrolysed with 20S NaOH al 40 C. I; is cooled to room témperature and neutralised with 20% HCl. The solvent is removed under red~ced pressure. The residue is purified by rec-ys~allisation (MeOH/H20) to obtain 24.1 g (63%) of a .
colourless solid.
lg : .
EX~p~,~ 32 ~ ~ -N, N ~ -bis-~2-hvdroxvethvl~ 3-rN-~2~3-dihvdroxvor carbamcv~ -methoxv~cetyl-~-(2-hvdroxvethvl~amino-2.4 6-t~iiodobenzovl-N-(2-hvdroxvethvl~a~inoacetv~ 2-hvdroxvethvl`-amino~-2 4 6-triiodoisoohtha}amide (lCJ - 491) Followin~ the general described for the compound of Example 2~ 16) and startin~ ~rom: 30 g (O.OZl mol) of the compound from Example 17, 42.3 g (0.111 mol) t~isodium phosphate dodeca-hydrate and 6.0 ml (7.2 g, 0.08~ mol) of 2-chloroethanol.
Yield: 45% m.p.: 220 -240-C
EXAMPLE 3~
N.N'-bis-(2,3-dihydroxy~roovll-5-~3-rN-t2,3-dihydroxv~roovl)-carbamovll-~-methoxyacetyl-N-(2-hvdrqxyethvl~amin~-~ 4 6-tri-3 5 ~ iodobenzoyl -N- ( 2-hydroxyethyl ) amLnoacetyl-~-( 2-hy~roxye~hyl ~ - . . amino)-2 4.6-triiodoisophthalamide ~ (lCJ - 631) '~ ~ ' : :
0 3 ~
a) N,N'-bis-~2,3-diacetoxypropyl)-5-chloroacetamido-2,4,6-triiodoisophthalamide To a solution of 87.3 g (0.1 mol) of 5-amino-N,N-bis-(2,3-diacetoxypropyl)-2,4,6-triiodo-isophthalamide in 260 ml of DMA, cooled to between 0-5 C, is slowly added 23.9 ml (33.9 g, 0.3 mol) acetoxyacetyl chloride. It is allowed to return to room temperature and is stirred for 5 - 6 hours. - -~
9 ml of water are added to des~roy the excess of acid chloride and it is poured into 1,250 ml of cold water. The water is decanted off and the grease that is formed is ' '' dissolved in 450 ml ethyl acetate. The water is extracted with 3 x 350 ml of AcOEt. The combined organic extracts are '' washed with : a) 2 x 250 ml 10% sodium bicarbonate solution ~' and b) 250 ml of a 10% sodium chloride solution. It is dried ' ' over anhydrous magnesium sulphate, filtered and the solvent ' removed under reduced pressure. The solid obtained is dried in vac~o.
Yield: 95 - 99% ~ ' m.p.: 190-205-C. ' "
b) N,N'-bis-(2,3-dihydroxypropyl)-5-~N-(2-hydroxyethyl)- ';
amino]acetamido-2,4,6-triiodoisophthalamide A solution of 9.50 g ~10 mmol) of the compound ~rom Example '''-33a) and 4.ag g (80 mmol) 2-aminoethanol in 20 ml of ethanol ; are heated overnight at 50 C. The mixture is cooled to room temperature, filtered and dried'in vacuo, with P2O5, to -obtain 7.7 g (95%) of a colourless solid with a m.p. = 216 30 ~ 220-C.
.:
c) N,N'-bi-~-(2,3-dihydroxypropyl)-5-(3-~N-(2,3-dihydroxypropyl) carbamoyl~-5-methoxyacetamido-2,4,6-triiodobenzoyl-N- '' (2-hydroxyethyl3aminoacetylamino)-2,4,6-triiodoisophthalamide To a solution of 30 g (17.2 mmol) of the compound from -~
Example 33b~ in 180 ml of DMA are added 10.01 g (17.2 mmol) --of the compound from Example la) and 21.3 g (74.4 mmol) of ' Na2C03.10H2O- The mixture is stirred vigorouSlY at 21003~8 room temperature overnight. It is filtered and the solvent is evaporated under reduced pressure until dryness. The residue is dissolved in lS0 ml of MeOH which is added to 90o ml of isopropyl alcohol. It is filtered off and dried in vacuo with P2O5. 50 g of a lightly coloured solid are obtained which is purified by breaking it up in 500 ml of isopropyl alcohol and refluxing for 1 hour. It is filtered and washed with ethyl ether (2 x 50 ml), and then dried in vacuo with P2O5 to obtain 41 g of a colourless solid.
These 41 g are dissolved in 200 ml of 50% aqueous methanol.
It is hydrolysed at 40 C with 20~ NaOH, cooled to room temperature and neutralised with 20~ HCl. The solvent is removed under reduced pressure (weight of residue 39 g). 60 -ml to 500 ml of isopropyl alcohol. After filtering and drying in vacuo with P2O5, 36 g (65%) of a colourLess solid are obtained.
d) N,N'bis(2,3-dihydroxypropyl)-5-~3-[N-(2,3-dihydroxypropyl) carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl)amino-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetyl-N-(2-hydroxy-ethyl)amino)-2,4,6-triiodoisophthalamide To a solution of 26 g (17.4 mmol) of the compound from Example 33c) in 65 ml of methanol, are added 34.8 g (91.52 mmol) of Na3P04.12H20. It is stirred for a short while and 7.35 g (91.29 mmol) o~ 2-chloroethanol are added and heated to 60-C. Stirring is continued at 60'C overnight. It is filtered and the alcoholic solvent is removed by evaporation under a reduced pressure. The residue (26.8 g) is purified by preparative liquid chromatography, to obtain ll g (40%) of a colourless solid.
, ' N N'-bis-t2.3-~ihydroxypropyll-5-~3-[N-t2.3-dihvdroxv rooyl) carbamoyll-5-hydroxyacetyl-N-~2-hydroxvethyllamino-2.4 6-triiodobenzo~aminoacetyl-N-(2-hydroxyethyl~amino~-2.4 6-triiQdoisophthalamide (lCJ - 791) :.. . . :.: ; - ; , . ~ ............ . . .
- . - , . . .
3 ~ ~
To a solution of 16 g (11.16 mmol) of the compound from Example 18, in 40 ml of methanol are added 22.3 g (58.70 mmol) of Na2P04.12H20. It is stirred for a short while and heated to 60~C, and 4.67 g (58.00 mmol) of 2-chloroethanol are added. Stirring is continued at 60 c overnight. It is then filtered and the alcoholic solvent is removed from the solution and washings by evaporation at reduced pressure. The -residue is purified by preparative liquid chromatography to obtain 8 g (47%) of a colourless solid.
N N'-bis-(2 3-hydroxypropyl~-5-l3- r N-(2.3-dihydroxypropyl)-carbamoyl1-5-methoxyacetyl-N-r2-hydroxyethyl)amino-2.4.6-tri-iQdobenzoyl-N-methylaminoacetyl-N-(2-hydroxyethyl~amino~-2~4~6 triiodoisophthalamide -~-(l~J - 1091) , a) N,N'-bis-(2,3-dihydroxypropyl)-5-methylaminoacetamido-2,4,6-triiodoisophthalamide 9.50 g (10 mmol) of N,N'-bis-(2,3-dihydroxypropyl)-5-chloro-acetamido-2,4,6-triiodo-isophthalamide, 20 ml of 33% ethanolic ~ -methylamine and 20 ml of ethanol, are heated at 40 C for ~ ;
hours. The reaction product dissolves in a short while, and during the course of the process precipitates abundantly.
It is ~iltered off and dried in vacuo with P205 to obtain 7 g (90%) of a colourless solid. -.. . .
b) N,N'-bis-(2,3-dihydroxypropyl?-5-(3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetamido~-2,4,6-triiodoisophthalamide To a~solution of 28.9 g (17.2 mmol) of the compound from Example 35a) in 180 ml of DMA are added 10.01 g (17.2 mmol) ---of the compound from Example la) and 21.3 g (74.4 mmol 03.10H20. It is stirred at 60 C overnight and the solvent is evaporated under reduced pressure until dryness . `~
The residue is dissolved in 120 ml of MeOH and added to 650 ~~~
.. . .
- ml of isopropyl alcohol. It is filtered and dried in vacuo .:
21003~8 with P2O5. 51.2 g of a slightly coloured solid are obtained. This solid is dissolved in 250 ml of 50% aqueous methanol and hydrolysed with 20% NaOH at 40 C. It is cooled to room temperature and neutralised with 20% HCl. The solvent is removed under reduced pressure (weight of residue 49 g), 150 ml of methanol are added and the methanolic solution is added to 650 ml of isopropyl alcohol. Once the addition has been ended, it is filtered. It is dried in vacuo con P2O5, to obtain 39 g (72%) of a colourless solid.
c) N,N'-bis-(2,3-dihydroxipropyl)-5-(3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl)amino-2,4,6-triiodobenzoyl-IN-methylaminoacetyl-N-(2-hydroxy-ethyl-amino)-2,4,6-triiodoisophthalamide To a solution of 31 g (21.2 mmol) of the compound from Example 35b) in 80 ml of methanol is added 42.4 g (111.51 ), 3 4 1 2 It is heated to reflux and 7.2 g (89.04 mmol) of 2-chloroethanol are added. Heating is continued with reflux overnight. It is filtered and the solvent removed under reduced pressure. The residue ~16.6 g) is purified by preparative liquid chromatography, to obtain 18 g ~55%) of a colourless solid.
EXAMpLE 36 N.N-bis-L2 3-dihydroxypropyl)-5-(3-~N-(2,3-dihydroxypropyl~
carbamQy~ _acetamido-2.4,6-triiodobenzoyl-N-(2 3-dihidroxy-propyLLaminoacetamido~-2~4.6- triiodoisophthalamide(lCJ-13sl) a) N-(2,3-diacetoxypropyl)-5-acetamido-2,4,6-triiodo-isophthalamic acid A mixture of 316 g (0.50 ml) N-(2,3-dihydroxypropropyl)-5-amino-2,4,6-triiodoisophthalamic acid, 3.2 ml concentrated sulphuric acid and 390 ml (421 g 4.12 mol) of acetic anhydride are refluxed in 1,200 ml of ethyl acetate. When the reaction has ended, the solid that is formed is filtered off, washed with ethyl ether and dried in vacuo to constant weight.
Yield: 93 % 210 0 3 ~ ~ :
M.p.: 263-264-C (d) . -: . -b) N-t2,3-diacetoxypropyl)-5-acetamidO-2,4,6-triiodo-isophthalamoyl chloride To a solution of 350 g (0.462 mol) of the compound described in Example 36a~ in 1,250 ml of DMA cooled to 5-10 c are slowly added 134 ml (219.6 g 1.85 ml) of thionyl chloride.
When the addition has ended, stirring is maintained at approximately 10 C for 1 hour, it is diluted with 3,000 ml of ethyl acetate and it is poured into 3,000 ml of water. The organic phase is separated and it the aqueous phase is -extracted with 2,000 ml of ethyl acetate. The combined organic phases are washed twice with 1,000 ml of a saturated ;
solution of sodium bicarbonate and once with 1,000 ml of a ~: ~
10% solution of sodium chloride. The extract is dried over ~ ~-anhydrous sodium sulphate, it is then filtered and treated for 2 hours with 30 g active carbon. It is~filtered and evaporated to dryness under reduced presion and the resulting residue is broken up by stirring with 2,000 ml of petroleum ether for 3 hours. It is filtered and dried in vacuo to constant weight.
: . ' , Yield: 90%
m.p.: 203-208-C (AcOEt) ~d) c) N,N-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl) carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-(2,3-di-hydroxypropyl)aminoacetamido)-2,4,6-triiodoisophthalamide It is obtained and purified following the same general procedure described for the compound from Example lb), starting from: 30 g (0.036 mol) of the compound described in Example 13b ) y 27.8 g (0.036 mol) of the N-(2,3- -~
diacetoxypropyl)-5-acetamido-2,4,6-triiodoisophthalamoyl chloride described in Example 36b).
Yleld: 45%
m.p.: 255-268~C~(d) -N.N'-~is-(2,3-dihydroxypropyl)-5-(3-~ 2,3-dihydroxvpropy~
carbamovL1-5-ac~tam~do-2.4.6-triiodobe~zoyl-N-methylacetyl-N-methvlamino~-2 4.6-triiodoisophthalamide (lCJ - 1491) 44.0 ~ (0.0S6 moles) of the compound from Example 36b ) and 47.~ g (0.056 moles) of the compound from Example described in llb) are dissolved in 264 ml of DMA. 32.04 g (0.11 moles) of Na2CO3.10H2O are added, and it is stirre~ at room tempe_ature for 20 hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated from isopropanol.
The product obtained (z 65.5 g) is dissolved in (1:1) met~anol/water and hydrolysed with 5% NaOH at 45-50 C. It is neut-alised and evaporated to dryness: The crude product obtained is purified by preparative liquid chromatography. 20 g of product are obtained.
Yield: 32.7% -20 m.pDecomposes and sinters from 160 C.
.
: - .
N.N'-~iS-Ll-hydroxymethyl-2.3-dihvdroxy~roovl)- 5-~3-rN-(2.3-hvdroxv~ro~vl)carbamovll-5-acetamido-2,4.6-triiodobenzovl-N-me~hylacetyl-N- methylamino)-2.4.6-triiodoi~ophthalamid~ v (lCJ - 1591) 50 g (5.5 x 10 2 moles) of the compound from Example 8a) and 42.83 g (5.5 x 10 2 moles) of the compound from Example 36b) are dissolved in 300 ml of DMA. 31.6 g (O.11 moles3 of - Na2CO3.10H2O are added and the mixture is stirred at room temperature for 20 hours. The insoluble salts are filtered off and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated from isopropanol. The product obtained (~ 69.2 q) is dissolved in (1:1) methanol/water and is hydrolysed with 5% NaOH at 45 -50-C.
It is neutralised and evaporated to dryness and the crude product obtained is purified by preparative liquid chromatography. 25.5 g Of product are obtained.
Yield: 30.8 ~ . m.p.: Sinters and decomposes above 170 C.
,Example 39 210 0 3 3 8 ~
N.N'-bis-(2,3-dihydroxypro~vl)-5-l3-~N-r2.3-dihvdroxv~ropyl) carbamoyl~-s-methoxyacetamido-2.4.6-triiodobenzoyl--N-(2-hvdroxy-3-methoxy~ropyl~aminoacetyl-N-methvlamino~''' ~2.4~6-triiodoiso~hthalamide. ~lCJ-l991) a) N,N'-bis-(2,3-dihydroxypropyl)-S-tN-(2-hydroxy-3-methoxy-propyl)aminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide ' ~ ' SO g (0.062 moles) of the compound from example lla) and 34.3 g (0.12 moles) of sodium carbonate decahidrate are suspended , in 350 ml of DMF. 22.3 g (0.24 moles) of 3-amino-1- , methoxy-2-propanol are added and the mixture is heated to ',- "
lS re~lux ~or 8 hours. It is then filtered and concentrated to dryness. The residue is dissolved in m~thanol an~ ' precipitated with isopropanol. 38 g (Yield: 71.~%) are obtained.
b) N,N'-bis-(2,3-dihydroxypropyl)-3-(3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-trliodo-' -benzoyl-N-(2-hydroxy-3-methoxypropyl)aminoace~yl-N-methyl- ~ ', amino~-2,4,6-triiodoisophthalamide. '~
30 g (0.035 moles) of 39a) and 28.39 g (0.035 moles~ o~ the ~ :-co~pound ~rom example la) are dissolved in 180 ml of DMA.
28.6 g (0.1 moles) of Na2C03.10H20 are added and stirred at ^l'"'"' ' room temperature for 20 h. It is ~iltered and the solution '~', is evaporated to dryness. The residue is dissolved in methanol and precipitated with isopropanol. The crude product ,' obtained is dissolved in (1:1) methanol/water and hydrolysed ' with 5% NaOH at 45 -50-C. It is then neutralised and -~ evaporated to dryness. The crude product obtained is purified by preparative liquid chromatography. 21 g (Yield:
; 38.7%) are obtained. ' Example 40 , , , ; N.N'-bis-(2.3-dihvdroxv~roDvl)-5-/3-rN-(2.3-dihydroxv~ro~yl~
arbamoyl)-5-~yd,~oxyacetvl-N-(,~m,çthoxy~thyl)amino-40 ~ 2.4.6-triiodobenzovlaminoacetyl-N-(2-methoxyethyl~amino)-2.4.~triioisophthalamide. (lCJ-2191) '.. . .
. _ . _ . . . . ... . . .
- 55 - ~
2~ ~338 This is prepared by following the general procedure described for the compound from Example 16) and starting from: 25 g (0.017 mol) of the compound from Example 18, 35.1 g (0.092 mol) of trisodium phosphate dodecahydrate and 6.9 g (0.0?3 mol) of 2-chloro-1-methoxyethane to obtain 20 g of the dimer sought, which is purified by preparative liquid chromatography.
Example 41 .' ' N,N'-~is-t2.3-dihydroxypropyl~-5-(3-rN-r2-hy~roxvethyl!--t~3-dihydroxv~ro~vl)carbamovll-5-methoxyacetamido-2.4,6-triiodobenzoyl-N-methylaminoacetyl-N-methvlamino~--2.4.6-triiodoisoDhthalamide. (lCJ-2291) a) N-(2-hydroxyethyl)-N-(2,3-dihydroxypropyl)-5-methoxy-acetamido-2,4,6-triiodoisophthalamoyl chloride To a cold solution of 23,37 g (35 mmol~ of 5-methoxy-acetamido-2,4,6-triiodoisophthaloyl chloride in 100 ml of DMF
are slowly added a solution of 4.55 g (45 mmol) of triethylamine and 6.08 g (45 mmol) of 2-hydroxyethyl-2,3-dihydroxypropylamin in 30 ml of DMF. Once the addition has been completed, it is heated to 10-15 C. It is s.irred for 2-3 hours and the reaction medium is distributed between 300 ml of ethyl acetate and 400 ml of water. The organic phase is decanted off and the aqueous phase is extracted with ethyl acetate (2x50 ml). The combined organic phases are washed with 5~ sodium bicarbonate ~lx50 ml) and saturated sodium chloride (lx50 ml). It is dried with anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The slightly coloured solid residue is dried in ~acuo with P2O5, to obtain 16.6 g (62%) of product.
b) N,N'-bis-(2,3-dihydroxypropyl)-5-(3-~N-(2-hydroxyethyl) N-(2,3-dihydroxypropyl)carbamoyl~-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~-2,4,6-triiodoisophthalamide. -' ' "
Following the general procedure described in example lb) ~ -. .
21~338 :
and starting with the compound described in 41a) (25 g, 32.6 mmol) and that described in llb) (25.7 g, 32.6 mmol), 33 g (66%) of a crude product is obtained, which is purified by preparative liquid chromatography. ~ -Example 42 N.N'-bis-(2-hydroxyethyl~-N,N'-bis-(2,3-dihydroxypropyl)-S-~3-[N-(2,3-dihydroxypropyl)carbamoyl)-5-acetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~- -2,4,6-triiodoisophthalamide. (lCJ-2391 a) N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxypropyl)- , 5-chloroacetyl-N-methylamino-2,4,6-triiodoisophthalamide 103 g (0.15 moles) of the compound from example 3a) are - -suspended in 30g ml of DMF. 85.8 g (0.3 moles) Na2C03.10H20 , are added and cooled to between 0 and 5 C. A solution of 40.5 g (0.3 moles) of 2-hydroxyethyl-2,3-dihydroxypropylamine in 90 ml of DMF are added, and the mixture is stirred at room temperature for 20 h. The solution is filtered and evaporated to dryness. The residue is dissolved in methanol and precipitated in ethyl ether. 96 g (72.4%) are obtained. ~-. .
b) N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxypropyl)-5-methylaminoacetyl-N-methylamino-2,4,6-triiodoisophthalamide ~ . .
60 g (0.068 moles) of the compound from example 42a) are dissolved in 420 ml of 33% methylamine in ethanol and stirred at room temperature for 2-3 days. The solution is evaporated to dryness and the residue is dissolved in methanol and precipitated from isopropanol. 42 g ,(Yield: 70.3%) are obtained.
.
c) N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxypropyl-5-~3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-acetamido-~; 2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino~-2,4,6-triiodoisophthalamide.
.
~ 40 35 g (0.04 moles) of the compound from example 42b) and ~ -.
31 g (0.04 moles) of the compound from example 36b) are dissolved in 210 ml of DMA. 34.3 g (0.12 moles) of Na2C03.10H2o are added and stirred at room temperature for hours. The mixture is filtered and the solution is evaporated to dryness. The residue is dissolved in methanol and precipitated with isopropanol. The crude product obtained is dissolved in (l:1) methanol/water and hydrolysed with 5% NaOH at 45-50~C. It is then neutralised and evaporated to dryness. The crude product obtained is purified by preparative liquid chromatography.
23 g (Yield: 37.5%) are obtained.
. .
.
:~, ::
. ~ .-
Claims (46)
1. Non-ionic dimeric compounds derived from aminotriiod isophthalic acid with the general formula I
I
where, R1 represents a linear or branched C2-C4 polyhydroxylalkyl radical;
R2 represents hydrogen, methyl or a linear C2-C3 polyhydroxyalkyl radical, or 2-hydroxy-3-methoxypropyl;
R3 and R8 are the same or different, and represent hydrogen, methyl or 2-hydroxyethyl;
R4 represents a linear or branched C2 to C4 polyhydroxy-alkyl radical;
R5 represents methyl, hydroxymethyl or methoxymethyl;
R6 and R7 are the same or different, and represent hydrogen, methyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.
R2 and R5 together form a group of the type where n can be 0 to 3.
I
where, R1 represents a linear or branched C2-C4 polyhydroxylalkyl radical;
R2 represents hydrogen, methyl or a linear C2-C3 polyhydroxyalkyl radical, or 2-hydroxy-3-methoxypropyl;
R3 and R8 are the same or different, and represent hydrogen, methyl or 2-hydroxyethyl;
R4 represents a linear or branched C2 to C4 polyhydroxy-alkyl radical;
R5 represents methyl, hydroxymethyl or methoxymethyl;
R6 and R7 are the same or different, and represent hydrogen, methyl, 2-hydroxyethyl or 2,3-dihydroxypropyl.
R2 and R5 together form a group of the type where n can be 0 to 3.
2. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetamido)-2,4,6-triiodoisophthal-amide.
3. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoylaminoacetamido)-2,4,6-triiodoisophthal-amide.
4. N,N'-bis-(hydroxymethyl-2,3-dihydroxypropyl)-5-(3[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoylaminoacetyl-N-methylamino)-2,4;6-tri-iodoisophthalamide.
5. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetyl-N-methylamino}-2,4,6-tri-iodoisophthalamide.
6. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-{3-[N-(1-hydroxymethyl-2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetamido}-2,4,6-triiodoisophthalamide.
7. N,N'-bis-(2,3-dihydroxypropyl)-3-{3-[N-(1-hydroxymethyl-2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetamido}-2,4,6-triiodoisophthalamide
8. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[N-(1-hydroxymethyl-2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetamido}-2,4,6-triiodoisophthalamide.
9. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)--5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
10. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
11. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[N-1-hydroxymethyl-2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
12. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-tri-iodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-tri-isdoisophthalamide.
13. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-2.3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodo-benzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodo isophthalamide.
14. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodo-benzoyl-N-(2,3-dihydroxypropyl)aminoacetamido}-2,4,6-triiodo-isophthalamide.
15. N,N'-bis-(2-hydroxyethyl)-5-{3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetamido}-2,4,6-triiodoisophthalamide.
16. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodo-benzoyl-N-(2,3-dihydroxypropyl)aminoacetamido}-2,4,6-triiodo-isophthalamide.
17. N,N'-bis-(2-hydroxyethyl)-5-{3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-hydroxyacetyl-N-(2-hydroxyethyl)amino-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetyl-N-(2-hydroxyethyl)amino}-2,4,6-triiodoisophthalamide.
18. N,N'-bis-(2-hydroxyethyl)-5-{3-[N-(2,3-dihydroxy-propyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetamido}-2,4,6-triiodoisophthalamide.
19. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodo-benzoylaminoacetamido}-2,4,6-triiodoisophthalamide.
20. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoylaminoacetamido}-2,4,6-triiodoisophthalamide.
21. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[ N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetamido}-2,4,6-triiodoisophthalamide.
22. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl) -5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetamido}-2,4,6-triiodo-isophthalamide.
23. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetamido}-2,4,6 triiodoisophthalamide.
24. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-(2,3-hydroxypropyl)carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-(2,3-dihydroxypropyl)aminoacetyl-N-methylamino}-2,4,6-tri-iodoisophthalamide.
25. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-triiodoisophthalamide.
26. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
27. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoylaminoacetyl-N-methylamino}-2,4,6-triiodo isophthalamide.
28. N,N'-bis-(2,3-dihydroxypropyl)-N,N'-dimethyl-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetyl-N-methylamino}-2,4,6-triiodo isophthalamide.
29. N,N'-bis-(2,3-dihydroxypropyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodo-benzoylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
30. N,N,N',N'-tetrakis-(2-hydroxyethyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
31. N,N,N',N'-tetrakis-(2-hydroxyethyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methylamino}-2,4,6-triiodoisophthalamide.
32. N,N,N',N'-tetrakis-(2-hydroxyethyl)-5-{3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodobenzoylaminoacetamido}-2,4,6-triiodoisophthalamide.
33. N,N'-bis-(2-hydroxyethyl)-5-{3-[N-(2,3-di-hydroxypropyl)carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl)-amino-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetyl-N-(2-hydroxyethyl)amino)-2,4,6-triiodolsophthalamide.
34. N,N'-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl)-amino-2,4,6-triiodobenzoyl-N-(2-hydroxyethyl)aminoacetyl-N-(2-hydroxyethyl)amino)-2,4,6-triiodoisophthalamide.
35. N,N'-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetyl-N-(2-hydroxy-ethyl)amino-2,4,6-triiodobenzoylaminoacetyl-N-(2-hydroxyethyl)-amino)-2,4,6-triiodoisophthalamide.
36. N,N'-bis-(2,3-dihydroxpropyl)-5-(3-[N-(2,3-di-hydroxypropyl)carbamoyl]-5-methoxyacetyl-N-(2-hydroxyethyl) amino-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-(2-hydroxy-ethyl)amino)-2,4,6-triiodoisophthalamide.
37. N,N-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-di hydroxypropyl)carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-(2,3-dihydroxypropyl)aminoacetamido)-2,4,6-triiodoisophthalamide .
38. N,N'-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-methylacetyl-N-methylamino)-2,4,6-triiodoisophthalamide.
39. N,N'-bis-(1-hydroxymethyl-2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-methylacetyl-N-methylamino3-2,4,6-triiodo-isophthalamide.
40. N,N'-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxyacetamido-2,4,6-triiodo-benzoyl-N-(2-hydroxy-3-methoxypropyl)aminoacetyl-N-methyl-amino)-2,4,6-triiodoisophthalamide.
41. N,N'-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-hydroxyacetyl-N-(2-methoxyethyl)-amino-2,4,6-triiodobenzoylaminoacetyl-N-(2-methoxyethyl)-amino)-2,4,6-triiodoisophthalamide.
42. N,N'-bis-(2,3-dihydroxypropyl)-5-(3-[N-(2-hydroxyethyl)-N-(2,3-dihydroxypropyl)carbamoyl]-5-methoxy-acetamido-2,4,6-triiodobenzoyl-N-methylaminoacetyl-N-methyl-amino)-2,4,6-triiodoisophthalamide.
43. N,N'-bis-(2-hydroxyethyl)-N,N'-bis-(2,3-dihydroxy-5-(3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-acetamido-2,4,6-triiodobenzoyl-N-methyl??i?oac??yl-N-methylamino)-2,4,6-triiodoisophthalamide.
44. Galenic compositions that include the compounds of general formula I, defined in Claim 1, in concentrations of between 100 and 400 mg of I/ml, and incorporating pH
stabilisers such as the buffer Tris (= tris(hydroxy-methyl)aminometane) and its salts, phosphates, citrates, and hydrogen carbonates, also sterile apyrogenic water, and may also incorporate complexing agents for heavy metals, -for example, the sodium and/or calcium salts of ethylene-diaminetetracetic acid, and other chelating agents which are pharmaceutically acceptable.
stabilisers such as the buffer Tris (= tris(hydroxy-methyl)aminometane) and its salts, phosphates, citrates, and hydrogen carbonates, also sterile apyrogenic water, and may also incorporate complexing agents for heavy metals, -for example, the sodium and/or calcium salts of ethylene-diaminetetracetic acid, and other chelating agents which are pharmaceutically acceptable.
45. Method for the preparation of compounds with the general formula I, defined in Claim 1, characterised by being formed by reacting a compound with the general formula II
II
with an acid chloride with the formula III
III
in the presence of a basic catalyst the radicals R1 to R8 having the significance indicated previously; during the reaction, the -OH groups are protected as acetates or, when the -OH groups are vicinal, as dioxolanes.
II
with an acid chloride with the formula III
III
in the presence of a basic catalyst the radicals R1 to R8 having the significance indicated previously; during the reaction, the -OH groups are protected as acetates or, when the -OH groups are vicinal, as dioxolanes.
46. A method for the preparation of compounds with the general formula I by means of an N-alkylation reaction using reagents 2-hydroxyethyl, 2-methoxyethyl, 2-hydroxy-3methoxy-propyl and 2,3-dihydroxypropyl chlorides in an alkaline medium, with the compounds of formula I in which R2 and R7 are hydrogen.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/ES1991/000080 WO1993010078A1 (en) | 1991-11-18 | 1991-11-18 | New non ionic iodized agents for x-ray contrasting method for preparing them and galenical compositions containing them |
| WOPCT/ES91/00080 | 1991-11-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2100338A1 true CA2100338A1 (en) | 1993-05-19 |
Family
ID=8270755
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002100338A Abandoned CA2100338A1 (en) | 1991-11-18 | 1992-11-17 | Non ionic iodized agents for x-ray contrasting, method for preparing them and galenical compositions containing them |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0571593B1 (en) |
| JP (1) | JPH06506478A (en) |
| AT (1) | ATE144766T1 (en) |
| AU (1) | AU665968B2 (en) |
| CA (1) | CA2100338A1 (en) |
| DE (1) | DE69214934T2 (en) |
| DK (1) | DK0571593T3 (en) |
| ES (1) | ES2095501T3 (en) |
| NO (1) | NO932549L (en) |
| NZ (1) | NZ245067A (en) |
| PT (1) | PT101076B (en) |
| WO (2) | WO1993010078A1 (en) |
| ZA (1) | ZA928856B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9419203D0 (en) * | 1994-09-23 | 1994-11-09 | Nycomed Innovation Ab | Contrast media |
| DE19510864A1 (en) * | 1995-03-16 | 1996-09-19 | Schering Ag | X-ray contrast media for computed tomography and urography |
| US5575905A (en) * | 1995-05-24 | 1996-11-19 | Nycomed Imaging As | Iodination process |
| DE19627309C2 (en) * | 1996-06-27 | 1999-07-29 | Schering Ag | Aqueous injectable formulations usable as contrast agents |
| EP4015509A1 (en) | 2020-12-18 | 2022-06-22 | Justesa Imagen S.A.U | Organometallic compounds and their use as multimodal contrasting media for imaging diagnosis |
| CN115806498A (en) * | 2021-09-15 | 2023-03-17 | 大道隆达（北京）医药科技发展有限公司 | Method for synthesizing 5-chloroacetamide-2, 4, 6-triiodo-isophthaloyl chloride |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4065553A (en) * | 1974-05-31 | 1977-12-27 | Laboratoires Andre Guerbet | X-Ray contrast media |
| AR207465A1 (en) * | 1974-05-31 | 1976-10-08 | Guerbet Lab Andre | PROCEDURE FOR THE PREPARATION OF TRIIODO-2,4,6- (TRIIODO-2,4,6-BENZOYL) -AMINO-ALKANOYLAMINOBENZOIC ACID DERIVATIVES FROM TRIIODO-2,4,6- (TRIIODO-2,4,6- (TRIIODO- 2,4,6-BENZOYL) -AMINOALKANOYLAMINOBENZOYL) -AMINO-ALKANOYL-AMINOBENZOIC AND OF TRIIODE-2,4,6-BIS ((TRIIODO-2,4,6-PHENYL) -CARBAMOYL-METHYL) -AMINOALKANOYL-AMINOBENZOIC ACID |
| DE2852094A1 (en) * | 1978-11-30 | 1980-06-12 | Schering Ag | NEW X-RAY CONTRASTING AGENTS |
| DE3038853A1 (en) * | 1980-10-10 | 1982-05-27 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | NEW N-HYDROXY-ALKYLATED DICARBONIC ACID-BIS- (3,5-DICARBAMOYL-2,4,6-TRIJODANILIDES), THEIR PRODUCTION AND THEIR CONTAINING X-RAY CONTRAST AGENTS (II) |
-
1991
- 1991-11-18 WO PCT/ES1991/000080 patent/WO1993010078A1/en unknown
-
1992
- 1992-11-10 NZ NZ245067A patent/NZ245067A/en unknown
- 1992-11-17 AU AU30872/92A patent/AU665968B2/en not_active Ceased
- 1992-11-17 AT AT92924727T patent/ATE144766T1/en not_active IP Right Cessation
- 1992-11-17 DE DE69214934T patent/DE69214934T2/en not_active Expired - Fee Related
- 1992-11-17 WO PCT/ES1992/000075 patent/WO1993010079A1/en active IP Right Grant
- 1992-11-17 JP JP5509010A patent/JPH06506478A/en active Pending
- 1992-11-17 CA CA002100338A patent/CA2100338A1/en not_active Abandoned
- 1992-11-17 ES ES92924727T patent/ES2095501T3/en not_active Expired - Lifetime
- 1992-11-17 ZA ZA928856A patent/ZA928856B/en unknown
- 1992-11-17 DK DK92924727.8T patent/DK0571593T3/en active
- 1992-11-17 EP EP92924727A patent/EP0571593B1/en not_active Expired - Lifetime
- 1992-11-18 PT PT101076A patent/PT101076B/en not_active IP Right Cessation
-
1993
- 1993-07-14 NO NO93932549A patent/NO932549L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO1993010078A1 (en) | 1993-05-27 |
| ES2095501T3 (en) | 1997-02-16 |
| NO932549D0 (en) | 1993-07-14 |
| ATE144766T1 (en) | 1996-11-15 |
| NZ245067A (en) | 1994-09-27 |
| EP0571593A1 (en) | 1993-12-01 |
| PT101076B (en) | 1999-10-29 |
| AU665968B2 (en) | 1996-01-25 |
| ZA928856B (en) | 1993-05-19 |
| DE69214934T2 (en) | 1997-02-27 |
| AU3087292A (en) | 1993-06-15 |
| EP0571593B1 (en) | 1996-10-30 |
| DK0571593T3 (en) | 1996-11-25 |
| EP0571593A4 (en) | 1993-09-17 |
| DE69214934D1 (en) | 1996-12-05 |
| JPH06506478A (en) | 1994-07-21 |
| NO932549L (en) | 1993-09-17 |
| WO1993010079A1 (en) | 1993-05-27 |
| PT101076A (en) | 1994-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5885548A (en) | Multiply substituted DTPA derivatives and their metal complexes, and their metal complexes, pharmaceutical agents that contain these complexes, their use in diagnosis and therapy, as well as process for the production of pharmaceutical agents | |
| US3701771A (en) | N-(2,4,6-triiodobenzoyl)-sugar amines | |
| JP5830589B2 (en) | Contrast agent | |
| ES2357861T3 (en) | CONTRAST AGENTS. | |
| DK158468B (en) | N-HYDROXYALCYLEDICED DICARBOXYLIC ACID BIS - (3,5-DICARBAMOYL-2,4,6-TRYODANANIDES AND CONTENTS OF CONTENTS | |
| IE62460B1 (en) | New dicarboxylic acid-bis-(3,5-dicarbamoyl-2,4,6-triiodoanilides), process for their production as well as x-ray contrast media containing them | |
| IE49948B1 (en) | Tri-iodised 5-aminoisophthalic acid derivatives | |
| WO1995001966A1 (en) | Iodinated oligomeric compounds and diagnostic compositions containing the same | |
| IE66460B1 (en) | 1,3-bis-[3-(mono- or poly-hydroxy)acylamino-5-(mono- or poly-hydroxyalkyl)aminocarbonyl-2,4,6-triiodo-benzoyl-amino]-hydroxy- or hydroxyalkyl-propanes their methods of preparation and X-ray contrast media containing them | |
| CA2100338A1 (en) | Non ionic iodized agents for x-ray contrasting, method for preparing them and galenical compositions containing them | |
| US6040432A (en) | Metal complexes, of DTPA derivatives suitable for use in diagnosis and therapy | |
| JP3249112B2 (en) | Nonionic compound and radiological contrast agent composition containing the compound | |
| AU654952B2 (en) | Novel X-ray contrast agents, compositions and methods | |
| KR970011452B1 (en) | Substituted dicarboxylic acids-bis(3,5-dicarbamoly-2,4,6-triiodo-anilides), and x-ray contrast agents containing them | |
| JPH0433786B2 (en) | ||
| CA1339666C (en) | Non-ionic polyol contrast media from ionic contrast media | |
| CA2154559A1 (en) | Derivated dtpa complexes, pharmaceuticals containing these compounds, their use as nmr and radiographic contrasting agents and process for producing the same | |
| EP0647618B1 (en) | New non ionic iodine-containing dimers useful as x-ray contrast agents, method for the preparation thereof, and galenical compositions containing them | |
| EP2129664A1 (en) | Trisubstituted triazamacrocycli c compounds and their use as contrast agents | |
| WO2009047315A1 (en) | Contrast agents | |
| WO1995026331A1 (en) | New non-ionic iodized dimers useful as x-ray contrasting agents, preparation process and pharmaceutical compositions containing them |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |